Obesity refers to an excessive total body fat content and/or increased local fat content with abnormal distribution. It is a chronic metabolic disease caused by the combined effects of genetic and environmental factors. Obesity mainly includes three characteristics: an increase in the number of fat cells, dysregulation of body fat distribution, and local fat deposition. According to the latest global study on BMI trends based on weight and height data from 128.9 million children, adolescents, and adults worldwide, the prevalence of obesity has increased in most countries from 1975 to 2016.

　　Global data published by The Lancet in 2014 shows that from 1975 to 2014, the ranking of obese adult men and women in China rose from 13th and 10th place respectively to 1st place worldwide. The "China Childhood Obesity Report" jointly released by Peking University School of Public Health and UNICEF in 2017 indicates that the detection rates of overweight and obesity among urban boys and girls aged 7 to 18 in China are as high as 28.2% and 16.4%, respectively, while in rural areas they are 20.3% and 12.8%, showing a rapid nationwide development trend. Throughout the past 2 to 3 million years of history, humans have been in a state of food shortage until the past few decades when hunger problems were significantly alleviated. However, the human energy metabolism system has not kept pace with the sudden abundance of food in recent decades, which may be one of the main reasons for the sharp rise in obesity rates.

　　1 List of Marketed Drugs

　　According to the "Primary Care Guidelines for Obesity (2019)", restricting calorie intake and increasing calorie expenditure are the preferred methods for preventing and treating overweight/obesity. Only patients with obesity who meet the criteria for drug treatment may consider medication. Currently, the obesity drugs approved by the US FDA mainly include naltrexone/bupropion, lorcaserin, phentermine/topiramate, orlistat, liraglutide, mazindol (withdrawn), and methamphetamine hydrochloride (withdrawn). However, in China, orlistat is the only drug approved by the National Medical Products Administration for obesity treatment, leaving a huge market gap.

　　Phentermine/topiramate (Qsymia®) is a weight-loss combination drug approved by the FDA in 2012 for patients with a BMI over 30 kg/m2 or over 27 kg/m2 with one or more obesity-related conditions such as hypertension, type 2 diabetes, and dyslipidemia. Qsymia® can reduce body weight by an average of 10%, while other marketed or previously marketed drugs generally only reduce weight by 5%. Its global sales are expected to reach $1.2 billion by 2028. Other marketed drugs are central small molecule drugs with poor selectivity, resulting in disproportionate side effects and efficacy, leading to unsatisfactory market acceptance.

　　Lorcaserin hydrochloride is a 5-hydroxytryptamine 5-HT2C agonist developed by Arena and first marketed in the US in June 2013 for obesity treatment. Its extended-release formulation was also approved in the US. However, in 2020, after safety study analyses concluded, the FDA required Eisai to withdraw the product from the market because the potential risks of lorcaserin outweighed its benefits. Mazindol is a sympathomimetic amine first marketed by Novartis in the US in 1973 as a short-term appetite suppressant for obesity. However, it was withdrawn from the market in 2002 for commercial reasons.

　　GLP-1 receptor agonists were first marketed as drugs for type 2 diabetes and have good weight loss effects while controlling blood sugar. Liraglutide was initially marketed as a diabetes drug and can reduce body weight by 5%. The FDA has approved it for obesity treatment. Currently, semaglutide and benaglutide are in phase 3 clinical trials for obesity treatment. The STEP4 trial is a randomized, double-blind, multicenter, placebo-controlled phase 3a clinical study lasting 68 weeks, aimed at verifying the efficacy of semaglutide in treating 902 patients with obesity or overweight with comorbidities. Patients in the trial first received 20 weeks of semaglutide treatment, during which the average weight decreased from 107.2 kg to 96.1 kg, then were randomly assigned to receive semaglutide or placebo treatment.

　　The trial results showed that all patients randomly assigned to semaglutide treatment lost an additional 7.9% of their baseline weight (96.1 kg), while the placebo group experienced a 6.9% weight regain. Patients continuously treated with semaglutide during the 68-week trial lost a total of 17.4% body weight. Benaglutide is a GLP-1 receptor agonist independently developed by Shanghai Renhui Biotech. The NMPA approved it for type 2 diabetes treatment in 2016. On May 17, 2019, the phase 3 clinical trial for benaglutide's weight loss indication officially started and was expected to complete by the end of 2020.

　　2 Global Obesity Drug Market

　　In the next five years, the North American market will remain the focus in the weight loss drug field, although Asia maintains high market growth expectations. Although obesity has become a global public health issue and the number of obese patients is increasing, less than 1% of obese patients currently receive drug treatment. The global obesity drug market size is only about $1.3 billion and is expected to grow to $3.44 billion by 2022 at a compound annual growth rate of 27.5%, depending on the proportion of obese patients using medication.

　　Forecasts indicate that the growth of the weight loss drug market in the next decade will mainly be driven by GLP-1 drugs such as liraglutide. Besides the marketed liraglutide, late-stage clinical drugs semaglutide, benaglutide, and tirzepatide also have huge market potential. Additionally, 13 GLP-1 drugs are in various early clinical stages.

　　Tirzepatide is a dual GIP and GLP-1 receptor agonist developed by Lilly, currently in phase III clinical development for subcutaneous treatment of type 2 diabetes, increased cardiovascular risk, patients inadequately controlled by diet and exercise alone, and adults with type 2 diabetes without obesity or overweight comorbidities.

　　HM-15211 is a long-acting GLP-1/glucagon/GIP triple agonist currently in phase II clinical trials at Hanmi for treating non-alcoholic steatohepatitis. The company is also conducting early clinical development for obesity. BI-456906 is a dual glucagon/GLP-1 agonist developed by Zealand Pharma, derived from the natural gut hormone oxyntomodulin. This compound is in phase II clinical development at Boehringer Ingelheim for subcutaneous treatment of obesity and type 2 diabetes. This product is the result of a research collaboration established in 2011 between Zealand Pharma and Boehringer Ingelheim. Glutazumab (GMA-102) is a humanized anti-GLP-1R monoclonal antibody with a GLP-1 variant in phase II clinical trials at Hongyun Huaining for treating type 2 diabetes and obesity.

　　3 China Weight Loss Drug Market

　　Currently, the only drug approved domestically for the treatment of obesity is Orlistat. Orlistat is a lipase inhibitor weight loss drug that reduces fat absorption by 30% by blocking the hydrolysis of triglycerides by lipase, thereby lowering calorie intake and causing an energy deficit. Compared to previously marketed appetite suppressants like Sibutramine and later drugs like Lorcaserin, Orlistat has very low systemic absorption after oral administration, does not affect the central nervous system or cardiovascular system, and is considered the safest weight loss drug. However, Orlistat's weight loss effect is inferior to recently marketed appetite suppressants such as Qsymia, and its clinical use is limited by digestive side effects caused by its mechanism of action, such as oily spotting and increased gastrointestinal flatulence.

　　In 2017, 2018, and 2019, sales in public hospitals and retail pharmacies were 330 million yuan, 490 million yuan, and 850 million yuan respectively. This shows that the domestic obesity drug market is still very limited.

　　Although GLP-1 class drugs have better safety and weight loss effects compared to Orlistat, these drugs are peptides or antibody products that require injection and are expensive. For example, Saxenda costs up to $1000 per month in the United States. Even if it can be marketed in China, the high out-of-pocket cost and the daily injection regimen will deter most people.

　　4 Drugs in Development

　　The Cortellis database shows that among drugs in development for obesity treatment, there is 1 registered product, 2 pre-registration, 2 phase III clinical trials, 17 phase II clinical trials, 25 phase I clinical trials, 2 INDs, and 20 preclinical. Plenity™ (Gelesis100) is a device composed of capsules containing superabsorbent biodegradable hydrogel particles, which was accepted by the FDA in 2019 to assist adult weight management. Thirteen GLP-1 drugs are in various early clinical stages. The company with the most obesity-related products is Novo Nordisk. Besides the marketed liraglutide, there are 4 drugs in development, including AM833, a human insulin acylated long-acting analog that reduces weight by decreasing energy intake. Its phase II clinical trial met the primary clinical endpoint: at 26 weeks, compared to an average baseline weight of 107.4 kg, patients in the AM833 4.5 mg dose group lost 10.8% of their weight, while the placebo group lost 3.0%, with the treatment difference being statistically significant. AM833 also showed good safety and tolerability.

　　Besides the popular targets GLP-1 and GIPR, there have been promising advances in neuropeptide Y5, sodium-dependent serotonin transporter, and melanocortin receptor ligands. Rhythm's main candidate drug setmelanotide is an MC4R agonist designed to restore impaired MC4R pathway function caused by genetic variations upstream of the receptor.

　　The US FDA has granted setmelanotide the "Breakthrough Therapy" designation for treating obesity related to genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway, including POMC deficiency obesity, LEPR deficiency obesity, Bardet-Biedl syndrome (BBS), and Alström syndrome. Tesofensine is a novel triple monoamine reuptake inhibitor that effectively inhibits the reuptake of neurotransmitters dopamine, norepinephrine, and serotonin in the synaptic cleft. In recent preclinical and clinical evaluations, Tesofensine has shown strong anti-obesity effects and is about to submit an NDA.

　　Domestic pharmaceutical company Hongyun Huaning Pharmaceutical has developed multiple products in the obesity field, including GMA-105, GMA-106, and GMA-108, with GMA-105 progressing faster and currently in phase II clinical trials. GMA-105 is the world's first antibody drug directly acting on GLP-1R, and thus the only new antibody molecule with targeted biased signaling. It is expected to activate downstream signaling pathways of the GLP-1 receptor on human cell surfaces by binding to the receptor, increasing GLP-1 levels, thereby regulating and affecting various functions related to human glucose metabolism in organs such as the central nervous system, pancreas, liver, and gastrointestinal tract. While promoting glucose metabolism in human cells, it induces satiety and reduces appetite, inhibits gastrointestinal motility and gastric acid secretion, suppresses appetite and food intake, delays gastric emptying, reduces food intake, and thus achieves weight loss. Shanghai Renhui Bio independently developed Benaglutide, which started phase III clinical trials for obesity in 2019.

　　5 Drugs in Development

　　Although the global epidemiology shows a continuously increasing base of obesity patients, the international market shows a patient medication rate of only about 1%, with a global drug market of only $1.3 billion. If the patient medication rate increases to 5% in the next decade, the global market could grow to $3.44 billion by 2022. Domestically, in the past three years, with only Orlistat in the weight loss field, although maintaining a high compound annual growth rate, the market capacity remains limited. In 2021, with the possible approval of GLP-1 drugs such as liraglutide, semaglutide, and benaglutide for obesity treatment, the market capacity may further expand.

　　However, we must also face the reality that the high price of GLP-1 drugs and the injection administration method may not be suitable for domestic obesity patients, and the medication rate still needs further observation.