Obesity refers to excessive total body fat content and/or increased local content and abnormal distribution. It is a chronic metabolic disease caused by a combination of genetic and environmental factors. Obesity mainly includes three characteristics: increased number of fat cells, imbalance of body fat distribution, and local fat deposition. According to the latest research on BMI trends in all countries around the world measured on the weight and height data of 128.9 million children, adolescents and adults, the prevalence of obesity in most countries around the world has increased between 1975 and 2016.
Global data released by the Lancet magazine in 2014 show that from 1975 to 2014, the world rankings of adult male and female obesity populations in my country rose from 13th and 10th to first in the world. In 2017, the “Report on Childhood Obesity in China” jointly issued by the School of Public Health of Peking University and UNICEF showed that the detection rates of overweight and obesity in urban men and women aged 7 to 18 in my country are as high as 28.2% and 16.4%, respectively, and 20.3% in rural areas And 12.8%, showing a rapid national development trend. In the past 2~3 million years of history, humans have been in a state of insufficient food supply. Until the last few decades, the problem of hunger has not been clearly resolved, but the human energy metabolism system has not kept up with the sudden increase in food for decades, This may be one of the main reasons leading to the sudden increase in obesity rates.
1 List of listed drugs
According to the "Guidelines for Primary Diagnosis and Treatment of Obesity (2019)", limiting calorie intake and increasing calorie consumption are the first choices for prevention and treatment of overweight/obesity. Only obese patients with medication indications can consider medication. At present, the main obesity drugs approved by the US FDA include cyproterone (naltrexone)/bupropion, lorcaserin, phentermine/topiramate, orlistat, liraru Peptides, mazindole (delisted) and methamphetamine hydrochloride (delisted). However, in my country, only orlistat is the only drug with indications for obesity treatment and approved by the National Food and Drug Administration, and there is a huge gap in the market.
Phentermine/topiramate (Qsymia®) is a weight loss compound preparation approved by the FDA in 2012 for BMI greater than 30kg/m2 and 27kg/m2 and accompanied by one or more obesity-related diseases such as hypertension, type 2 diabetes and Dyslipidemia. Qsymia® can reduce body weight by an average of 10%. Other drugs in the market and once in the market can generally only reduce body weight by 5%. It is estimated that its global sales will reach US$1.2 billion in 2028. Other drugs on the market are central small molecule drugs with poor selectivity, so side effects and curative effects are out of proportion, leading to unsatisfactory market absorption.
Lorcaserin 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. A sustained-release formulation of the product has also been approved in the United States. However, in 2020, after the conclusion of the analysis of the safety study, the FDA required Eisai to withdraw the product from the market, and the potential risks of lorcaserin outweigh its benefits. Maindole is a sympathomimetic amine, first listed in the United States by Novartis in 1973 as a short-term appetite suppressant for obesity, However, due to commercial reasons, the product was withdrawn from the market in 2002.
GLP-1 receptor agonist was first used in the marketing of type 2 diabetes drugs, which has a good weight loss effect while controlling blood sugar. Liraglutide is marketed as a diabetes drug and can reduce body weight by 5%. The FDA has approved it for the treatment of obesity. At present, simeglutide and benaglutide have been used in phase 3 clinical treatment for obesity. The STEP4 trial is a randomized, double-blind, multi-center, placebo-controlled Phase 3a clinical study. The trial lasted for 68 weeks to verify the efficacy of simeglutide in the treatment of 902 obese or overweight comorbidities. Efficacy. The patients participating in the trial were first treated with simeglutide for 20 weeks, and after their average body weight was reduced from 107.2 kg to 96.1 kg, they were randomly assigned to receive simeglutide or placebo treatment.
The results of the trial showed that the average weight of all patients randomized to receive simeglutide treatment was an additional 7.9% less than the baseline (96.1 kg), while the weight of patients in the placebo group rebounded by 6.9%. During the 68-week trial period, patients who had been treated with simeglutide lost a total of 17.4%. Benaglutide is a GLP-1 receptor agonist drug independently developed by Shanghai Renhui Biology. NMPA was approved for the treatment of type 2 diabetes in 2016. Benaglutide was indicated for weight loss on May 17, 2019. The Phase III clinical study was officially launched and is expected to be completed by the end of 2020.
2Global obesity drug market
In the next 5 years, the North American market will still be the focus of the field of weight-loss drugs, although the Asian region maintains high market growth expectations. Although the obesity rate has become a global public health problem, and the number of obese patients is increasing, less than 1% of obese patients currently receive drug treatment, and the global obesity drug market is only about 1.3 billion U.S. dollars. It is expected to be 2022 Will grow to 3.44 billion US dollars at a compound annual growth rate of 27.5%. This depends on the proportion of obese patients taking medication.
The forecast shows that the growth of the weight loss drug market in the next ten years is mainly due to GLP-1 drugs such as liraglutide. In addition to the marketed liraglutide, simeglutide, benaglutide and Tirzepatide in the late clinical stage also have huge market potential. At the same time, there are 13 GLP-1 drugs in the early clinical stage at different stages. .
Tirzepatide is a GIP and GLP-1 dual receptor agonist developed by Lilly. It is undergoing phase III clinical development for subcutaneous treatment of type 2 diabetes with increased cardiovascular risk, patients with insufficient diet and exercise control alone, and adults without obesity or Type 2 diabetes patients with overweight complications.
HM-15211 is a long-acting GLP-1/glucagon/GIP triple agonist, currently undergoing phase II clinical trials in Hanmi for the treatment of non-alcoholic steatohepatitis. The company is also in early clinical development for obesity. BI-456906 is a dual-effect glucagon/GLP-1 agonist developed by Zealand Pharma, derived from the natural intestinal hormone hydroxymodulin. The compound is undergoing phase II clinical development at Boehringer Ingelheim for subcutaneous treatment Patients with obesity and type 2 diabetes. This product is the product 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 the phase II clinical trial of Hongyun Huaning for the treatment of type 2 diabetes and obesity.
3 China's diet drug market
At present, the only drug approved for obesity treatment in China is Orlistat. Orlistat is a lipase inhibitor type weight loss drug. By blocking the hydrolysis of triglycerides by lipase, the absorption of fat is reduced by 30%, thereby reducing the level of calorie intake and causing energy deficit. Compared with the previously marketed sibutramine and the later marketed appetite suppressants such as lorcaserin, the systemic absorption level of orlistat after oral administration is extremely low, does not affect the central nervous system and cardiovascular system, and is considered the most Safe weight loss pills. However, orlistat's weight loss effect is not as good as Qsymia and other appetite suppressants marketed in recent years, and gastrointestinal adverse reactions such as oily spots caused by its own mechanism of action and increased gastrointestinal exhaust also limit the clinical application of the drug.
The sales of public hospitals and retail pharmacies in 2017, 2018 and 2019 were 330 million yuan, 490 million and 850 million yuan, respectively. This shows that the domestic obesity drug market is still very limited.
Although GLI-1 drugs have better safety and weight loss effects than orlistat, these drugs are peptides or antibody products that require injections and are relatively expensive. Take Saxenda as an example. The cost of medication in the United States is as high as US$1,000 per month. Even if it can be marketed in China, the high out-of-pocket costs and the once-a-day administration method will discourage most Chinese people.
4 Drugs under development
According to the Cortellis database, the drug under development for the treatment of obesity includes 1 registered product, 2 pre-registered, 2 phase III clinical, 17 phase II clinical, 25 phase I clinical, 2 IND, and 20 preclinical . Plenity TM (Gelesis100) is a device consisting of capsules containing superabsorbent biodegradable hydrogel particles. The device has been accepted by the FDA in 2019 to help adults manage weight. 13 GLP-1 drugs are in different early clinical stages. The company with the most layout in the obesity field is Novo Nordisk. In addition to the listed liraglutide, there are 4 products under research. Among them, AM833 is a long-acting analog of human amylin, which can reduce Energy intake reduced body weight, and its phase II clinical study reached the primary clinical endpoint. Compared with an average baseline body weight of 107.4 kg at 26 weeks, patients in the AM833 4.5 mg dose group lost 10.8%, while patients in the placebo group lost weight 3.0%, the treatment difference is statistically significant, and AM833 is safe and well tolerated.
"In addition to popular targets GLP-1 and GIPR, neuropeptide Y5, sodium-dependent serotonin transporter, melanocortin receptor ligands, etc. also have gratifying progress. Rhythm’s main drug candidate, setmelanotide, is an MC4R agonist designed to restore the damaged MC4R pathway function caused by genetic mutations occurring upstream of the receptor.
The US FDA has awarded setmelanotide the title of "Breakthrough Therapy" for the treatment of obesity related to genetic defects in the MC4 receptor upstream of the leptin-melanocortin pathway, including POMC deficiency obesity, LEPR deficiency obesity, Bardet -Biedl syndrome (BBS) and Alström syndrome. Tesofensine is a new triple monoamine reuptake inhibitor, which can effectively inhibit the reuptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine and serotonin. In recent preclinical and clinical evaluations, Tesofensine has shown strong anti-obesity effects and will be submitted to NDA soon.
The domestic pharmaceutical company Hongyun Huaning Pharmaceutical has deployed multiple products in the field of obesity, GMA-105, GMA-106 and GMA-108, among which GMA-105 is progressing rapidly and is in clinical phase II. GMA-105 is the world's first antibody drug that directly acts on GLP-1R, so it is also the only new antibody molecule with a targeted information transmission preference (Bias). It is expected to interact with GLP-1 on the surface of human cells. The receptors are combined to activate the downstream signaling pathways of the receptors in the cell, and increase the level of GLP-1, thereby regulating and affecting different organs including the central nervous system, pancreas, liver and gastrointestinal tract, which are related to human glucose metabolism. The various functions of the human body can promote the human body's cell sugar metabolism, at the same time make the human body feel full and appetite decrease, inhibit gastrointestinal peristalsis and gastric juice secretion, inhibit appetite and ingestion, delay gastric emptying, reduce human food intake, and realize relief The purpose of weight. Benaglutide, self-developed by Shanghai Renhui Biology, launched a phase III clinical study on obesity in 2019.
5 drugs under development
Although from a global epidemiology point of view, the base of obese patients is rising, the international market shows that the rate of drug use by patients is only about 1%, and the global drug market is only $1.3 billion. If the rate of drug use by patients increases to 5% in the next ten years, The global market may increase to 3.44 billion US dollars by 2022. In the past 3 years in the country where there was only orlistat in the field of weight loss, although it has maintained a high compound annual growth rate, the market capacity is still limited. In 2021, it may face liraglutide, simeglutide and benzalkonium. GLP-1 drugs such as naglutide are approved for the treatment of obesity, and the market capacity may be further enlarged.
But we also have to look at the current situation, the high price of GLP-1 drugs and whether the injection method is suitable for obese patients in China, and the proportion of drugs used needs further observation.