Obesity refers to excessive total fat content and/or local fat content increase and abnormal distribution. It is a chronic metabolic disease caused by genetic and environmental factors. Obesity mainly includes three characteristics: increased number of fat cells, imbalance of body fat distribution and local fat deposition. The prevalence of obesity increased in most countries between 1975 and 2016, according to a new study of BMI trends in all countries, based on weight and height data for 128.9 million children, adolescents and adults.
　　Global data released by the Lancet in 2014 show that from 1975 to 2014, China's adult male and female obesity population rose from 13th and 10th in the world respectively to 1st in the world. In 2017, the School of Public Health of Peking University and the United Nations Children's Fund jointly released the "China Childhood Obesity Report" shows that the detection rate of overweight and obesity in urban men and women aged 7 to 18 is as high as 28.2% and 16.4%, respectively, and 20.3% and 12.8% in rural areas, showing a rapid development trend across the country. In the past two to three million years of history, human beings have been in a state of insufficient food supply, and the hunger problem has been significantly solved in recent decades, but the human energy metabolism system has not kept up with the pace of sudden abundance of food in recent decades, which may be one of the main reasons for the sudden rise in obesity rates.
　　1 List of listed drugsAccording to the Guidelines for Primary Care and Treatment of Obesity (2019), caloric restriction and increase in caloric expenditure are the preferred options for the prevention and treatment of overweight/obesity, and only obese patients with indications for drug therapy should be considered for drug therapy. At present, the main drugs approved by the United States FDA for the treatment of obesity are cipromedromorphone (naltrexone)/bupropion, lorcathrin, phentamine/topiramate, orlistat, lilaglutide, marindole (withdrawn) and methamphetamine hydrochloride (withdrawn). However, at present, there are only orlistat drugs approved by the National Food and Drug Administration for obesity treatment in China, and there is a huge gap in the market.
　　Phentermine/topiramate (Qsymia®) is a weight-loss combination approved by the FDA in 2012 for BMI greater than 30kg/m2 and 27kg/m2 with one or more obesity-related conditions such as hypertension, type 2 diabetes, and dyslipidemia. Qsymia® reduces body weight by an average of 10%, compared to 5% for other marketed and formerly marketed drugs, and is expected to achieve global sales of $1.2 billion by 2028. Other marketed drugs are central small molecule drugs with poor selectivity, so side effects and efficacy are disproportionate, leading to unsatisfactory market absorption.
　　Lorcasserin hydrochloride is a serotonin 5-HT2C agonist developed by Arena and first marketed in the United States in June 2013 for the treatment of obesity. An extended-release formulation of the product has also been approved in the United States. However, in 2020, the FDA asked Eisai to remove the product from the market after an analysis of safety studies concluded that the potential risks of lorcasserin outweighed its benefits. Marindole is a sympathomimetic amine that was first marketed in the United States in 1973 by Novartis as a short-term appetite suppressant to combat obesity. However, the product was withdrawn from the market in 2002 for commercial reasons.
　　GLP-1 receptor agonists were first marketed as type 2 diabetes drugs and have good weight loss effects while controlling blood sugar. Liraglutide is marketed as a diabetes drug that can reduce body weight by up to 5% and has been approved by the FDA for the treatment of obesity. At present, smerlutide and Benarlutide have been used in phase 3 clinical treatment of obesity. The STEP4 trial is a 68-week randomized, double-blind, multicenter, placebo-controlled, phase 3a trial designed to test semerlutide in 902 patients who are obese or have overweight comorbid conditions. Patients in the trial were treated with semerlutide for 20 weeks and were randomly assigned to receive semerlutide or placebo after their average weight decreased from 107.2 kg to 96.1 kg.
　　The results of the trial showed that all patients randomized to semerlutide lost an additional 7.9% of their average body weight from baseline (96.1 kg), while patients in the placebo group regained 6.9% of their weight. Patients who had been receiving semerlutide during the 68-week trial lost a total of 17.4 percent of their body weight. Benarutide is a GLP-1 receptor agonist drug independently developed by Shanghai Renhui Biology. NMPA has been approved for the treatment of type 2 diabetes in 2016. The Phase III clinical study of Benarutide weight loss indication was officially launched on May 17, 2019, and is expected to be completed by the end of 2020.
　　2 Global obesity drug marketIn the next five years, the North American market will remain the focus of the weight loss drug field, although the Asian region maintains a high market growth expectation. Although the obesity rate has become a global public health problem, the number of obese patients is rising, but currently less than 1% of obese patients receive drug treatment, the global obesity drug market size is only about 1.3 billion US dollars, is expected to grow at a compound annual growth rate of 27.5% to 3.44 billion US dollars by 2022. It depends on the proportion of people who are obese.
　　The forecast shows that the growth of the weight loss drug market in the next decade is mainly due to GLP-1 drugs such as Liraglutide. In addition to Liraglutide, which is already on the market, the late-clinical semerlutide, Benarlutide and Tirzepatide also have great market potential, while there are 13 GLP-1 drugs in various stages of early clinical stages.
　　Tirzepatide, Lilly's GIP and GLP-1 double receptor agonist, is in Phase III clinical development for the subcutaneous treatment of type 2 diabetes in patients with increased cardiovascular risk, inadequate diet and exercise control alone, and adults with type 2 diabetes without obesity or overweight comorbiditis.
　　HM-15211 is a long-acting GLP-1 / glucagon/GIP triple agonist currently in Phase II clinical trials at Hanmi for the treatment of non-alcoholic steatohepatitis. The company is also in early clinical development for obesity. BI-456906 is a dual-acting glucagon/GLP-1 agonist developed by Zealand Pharma, derived from the natural gut hormone hydroxyregulin, which is in Phase II clinical development at Boehringer Ingelheim for the subcutaneous treatment of patients with obesity and type 2 diabetes. The product is the result of a research collaboration between Zealand Pharma and Boehringer Ingelheim established in 2011. Glutazumab (GMA-102) is a humanized monoclonal antibody against GLP-1R with a GLP-1 variant in Phase II clinical trials for the treatment of type 2 diabetes and obesity.
　　3 China's diet drug marketAt present, the only drug approved for obesity treatment in China is orlistat. Orlistat is a lipase inhibitor class of weight loss drugs. By blocking the hydrolysis of triglycerides by lipase, the amount of fat absorption is reduced by 30%, and then the level of caloric intake is reduced, resulting in energy deficit. Compared with appetite inhibitors such as Sibutramine and lorcasserin, orlistat has a very low level of systemic absorption after oral administration, does not affect the central nervous system and cardiovascular system, and is considered to be the safest weight loss drug. However, the weight loss effect of orlistat is not as good as that of appetite inhibitors such as Qsymia, which have been listed in recent years, and the gastrointestinal adverse reactions such as oily spots and increased gastrointestinal exhaust caused by its own mechanism of action also limit the clinical application of orlistat.
　　In 2017, 2018 and 2019, the sales of public hospitals and retail pharmacies were 330 million yuan, 490 million yuan and 850 million yuan, respectively. Thus, the domestic obesity drug market is still very limited.
　　Although GLI Class 1 drugs have better safety and weight loss effect than orlistat, this class of drugs are peptide or antibody products, which need to be injected, and the price is high, taking Saxenda for example, the drug cost in the United States is as high as 1,000 US dollars/month, even if it can be marketed in China. High out-of-pocket costs and once-a-day injections would also deter most people.
　　4 Developing drugsThe Cortellis database shows that the drugs in research for the treatment of obesity include 1 registered product, 2 pre-registration, 2 phase III clinical trials, 17 phase II clinical trials, 25 phase I clinical trials, two IND trials, and 20 pre-clinical trials. Plenity TM (Gelesis100) is a device consisting of capsules containing ultra-absorbent biodegradable hydrogel particles that was accepted by the FDA in 2019 to aid in adult weight management. Thirteen GLP-1 drugs are in various early clinical stages. Novo Nordisk has the largest presence in the field of obesity. In addition to Liraglutide, it has four products under development. Among them, AM833 is a long-acting analogue of human amylin acylation, which can reduce body weight by reducing energy intake. The Phase II clinical study achieved the primary clinical endpoint. Patients in the 4.5mg dose group of AM833 lost 10.8% of their body weight, while those in the placebo group lost 3.0%. The treatment difference was statistically significant, and AM833 was safe and well tolerated.
　　In addition to the popular targets GLP-1 and GIPR, neuropeptide Y5, sodium-dependent serotonin transporter, and melanocortin receptor ligands have also made promising progress. Rhythm's lead drug candidate, setmelanotide, is an MC4R agonist designed to restore impaired MC4R pathway function caused by genetic variations occurring upstream of the receptor.
　　The FDA has awarded setmelanotide a "Breakthrough therapy therapy" designation for the treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway, including POMC deficiency obesity, LEPR deficiency obesity, and LEPR deficiency obesity. Bardet-Biedl syndrome (BBS) and Alstrom syndrome. Tesofensine is a novel triple monoamine reuptake inhibitor that effectively inhibits the reuptake process in the synaptic gap of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations, Tesofensine has shown a strong anti-obesity effect and is about to submit an NDA.
　　Hongyun Huining Pharmaceutical, a domestic pharmaceutical company, has laid out a number of products in the field of obesity, GMA-105, GMA-106 and GMA-108, of which GMA-105 has made rapid progress and is in clinical phase II. GMA-105 is the first antibody drug in the world that directly acts on GLP-1R, and therefore the only new antibody molecule with targeted information transmission Bias, which is expected to activate the downstream signaling pathway of the receptor in the cell by binding to the GLP-1 receptor on the surface of human cells, and increase the level of GLP-1. Thus, it regulates and affects various functions related to human sugar metabolism in different organs, including the central nervous system, pancreas, liver and gastrointestinal tract, etc., while promoting human cell sugar metabolism, it makes human body feel full and appetite decrease, inhibits digestive peristalsis and gastric secretion, inhibits appetite and eating, delays gastric emptying, reduces human food intake, and thus achieves the purpose of weight loss. Benarutide, self-developed by Shanghai Renhui Biology, started a Phase III clinical study in obesity in 2019.
　　5 Developing drugsAlthough from the perspective of global epidemiology, the patient base of obesity is rising, but the international market shows that the patient drug use rate is only about 1%, the global drug market is only 1.3 billion US dollars, if the patient drug use rate increases to 5% in the next decade, the global market may increase to 3.44 billion US dollars by 2022. In the past three years, only orlistat in the field of weight loss in China has maintained a high compound annual growth rate, but the market capacity is still limited, and in 2021, GLP-1 drugs such as Liraglutide, Smerlutide and Benarlutide may be approved for the treatment of obesity, and the market capacity may be further enlarged.
　　However, we also have to see clearly the current situation, the high price of GLP-1 drugs and the injection method are suitable for domestic obesity patients, and the proportion of drugs needs to be further observed.