glucagon-like peptide-1 receptor (GLP-1R) agonists are becoming the mainstream development direction of obesity, and weight loss data are constantly refreshed with the emergence of iterative products.
, first smegglutide developed by Novo Nordisk , defeated the same product liraglutide , becoming a new generation of innovative weight loss drugs. Later, Eli Lilly's GLP-1R/GIPR dual-target agonist telpopeptide achieved a weight loss effect of 22.5%, exceeding the weight loss history set by smegglutide. The synergistic effect of the dual target of
seems to lead to better weight loss effects. Domestic companies have Innovent Biologics announced that its GLP-1R/GCGR dual agonist mazdutide (IBI362) has obtained positive phase II data. Not only that, the compound preparation cagriSema developed by Novo Nordisk combined with amylin and GLP-1 has achieved effective weight loss efficacy in phase II clinical practice. The weight loss track led by
GLP-1 has expanded from a single target to dual and triple receptor agonists, and has extended from a compound preparation combined with GLP-1 to potential innovative pathways such as amylin, GDF15, and cheesophagin.
GLP-1RA leads the weight loss track
Currently, GLP-1R agonists approved for the treatment of obesity in the world include Saxenda (liraglutide) and Wegovy (smegglutide), which were approved by FDA in 2014 and 2021, respectively, and were both developed by Novo Nordisk. The fastest-progress in R&D in China is Renhui Bio's benaglutide (HYBR-014), which submitted an application for listing for obesity indications in March 2022.
GLP-1R has become a popular target for weight loss indications, mainly attributed to the mechanistic characteristics of GLP-1 itself and the weight loss efficacy shown by liraglutide and semegglutide.
study shows that GLP-1R agonists can not only promote the secretion of insulin and play a role in lowering glycemic, but also effectively delay gastric emptying of , reduce intestinal motility, activate neural pathway and appetite regulation area of the hypothalamus, reduce appetite and reduce food intake, thereby treating obesity. Data from Novo Nordisk's Phase III clinical trial showed that after the 56-week treatment period, about 62% of obese patients lost 5% of their weight and 34% of their patients lost 10%. This data supports the product to be launched in 2014, becoming the first GLP-1 weight loss drug to be approved. In addition, liraglutide has also expanded its age to 12 years of age and above in 2020. After the 56-week treatment period, the BMI standard deviation score (BMI SDS) in the liraglutide group decreased by an average of 0.23, and there was no change in the placebo group.
semegglutide is another GLP-1 product developed by Novo Nordisk, with a weight loss effect better than liraglutide. In five trials of STEP 1, 3, 4, 5 and 8, the average weight loss of obese patients treated with semegglutide 2.4 mg was 16.9% to 18.2% over 68 weeks, and maintained a weight loss level of 16.7% during the 2-year treatment period. Compared with the weight loss of 6.6% of biliraglutide, semegglutide lost 17.1% of patients. The excellent weight loss effect of
two GLP-1 products has brought good sales performance to Novo Nordisk. In the first three quarters of 2022, the sales of Danish kroner (about RMB 11.13 billion), with increasing 491% year-on-year.
's significant weight loss effect and considerable economic benefits have also attracted domestic companies to compete to enter the GLP-1 field. In addition to Renhui Bio, which has applied for marketing, GZR18 of Ganli Pharmaceutical, TG103 of Shiyao Group, Noli glycopeptide of Hengrui Pharmaceutical and GMA105 of Hongyun Huaning all progressed to the Phase II clinical stage respectively. In terms of generic drugs for
, five domestic companies have developed obesity indications for liraglutide biosimilars. Huadong Pharmaceutical has made the fastest progress. Its products were applied for the market in July this year. Jiangsu Wanbang, a subsidiary of Fosun Pharmaceutical, has advanced to the Phase III clinical stage. First, Weida Bio's ecnoglutide (XW003) has advanced to Phase II clinical stage. In addition, there are Jiuyuan Gene and Nobote Bio. No company has yet to develop obesity in the development of semegglutide biosimilars.
Although liraglutide has not been approved for weight loss in China, liraglutide has been included in the category of super manual use of overweight/obesity in the "Catalogue of Super Instructions for Drug Use (2020 Edition)" released by Guangdong Pharmaceutical Society . The fierce competition in the
weight loss track has also attracted companies to find other oral dosage forms in order to gain a head advantage.For example, XW004 developed by Yida Bio is an oral preparation of ecnoglutide and is in Phase I clinical practice. Hengrui Medicine's SHR-2042 and Xinlitai Pharmaceutical's SAL0112 are both oral GLP-1 analogs and have obtained clinical approval from the National Medical Products Administration.
For foreign companies, the oral dosage form of semegglutide developed by Novo Nordisk is in the phase IIIa clinical stage and is expected to end trials in the first half of 2023. Pfizer two oral small molecule GLP-1R agonists danuglipron (PF-06882961) and PF-07081532 are both in phase II clinical practice. Eli Lilly has also laid out a LY3502970 and is conducting phase II research on obesity. No effective data on oral GLP-1RA in obesity have been observed.
dual agonist or compound preparations counterattack
develops iterative products based on single GLP-1RA, and has become a popular competitive direction for domestic and foreign companies. For example, dual agonists or compound preparations can exert the synergy of multiple targets, optimize weight loss effects, and reduce side effects.
Eli Lilly leads the development of dual receptor agonists, and GLP-1R/GIPR dual agonist tilpopeptide showed a significant weight loss effect that exceeded semegglutide in the phase III trial results of SURMOUNT-1. Specifically, after 72 weeks of texipatide, the average weight loss ratio of subjects in the 5 mg, 10 mg and 15 mg dose groups reached 16%, 21.4%, and 22.5%, respectively. In terms of domestic companies, the GLP-1R/GCGR dual agonist mazdutide (IBI362) introduced by Innovent Biologics from Eli Lilly has made the fastest progress, and recently launched the Phase III GLORY-1 clinical study. Previously, mazdutide had obtained positive phase II data in the low-dose group, reaching the main endpoints in the 3mg, 4.5mg and 6mg doses, with the weight loss of subjects reaching 7.21%, 10.56% and 11.57%, respectively. Phase II clinical practice of high-dose 9mg and 10mg is still in progress.
Except Innovent Biologics, the GLP-1R dual agonists developed by other companies are in the early stages, and most of them choose 2 diabetes as the first development indication, and only a few companies have expanded to obesity. GLP-1R/GIPR agonist: GMA106 from Hongyun Huaning is undergoing phase I clinical trials in Australia, and HS-20094 of hausen Pharmaceutical has been approved by clinical IND.
In addition, there is the GLP-1R/FGF21 dual-target agonist of Dongyangguang Pharmaceutical and the GLP-1R/GCGR/FGF21R three-target agonist DR10624, which was first developed by Doyle Bio. Phase I clinical research is being carried out for the treatment of obesity.
Ruisui Bank analysts expect Eli Lilly's terpole peptide sales to exceed $14 billion in 2030. Novo Nordisk, who has two heavy weight loss products, will never miss the dual target field. In fact, Novo Nordisk launched the GLP-1R dual agonist in 2015, but has terminated the research and development of multiple projects for various reasons, including NN-6177, NN9709, NNC0090-2746 (RG-7697) and NN9423. Novo Nordisk, which failed in the dual-target field, turned to the development of composite preparations. In August, Novo Nordisk announced that the Phase II clinical trial of the compound preparation cagriSema has achieved positive results, achieving effective therapeutic effects on reducing glycemic and weight loss. After 32 weeks of treatment, the weight loss in the cagriSema group, the semegglutide group and the cagrilintide group reached 15.6%, 5.1% and 8.1%, respectively.
CagriSema is a dual-complex preparation of long-acting amylin analogs cagrilintide and semegglutide, which has been approved in China for obesity/overweight.
develops a variety of potential targets
Whether it is a single-target preparation for GLP-1, dual-, triple agonists and complex preparations, they are all developed around GLP-1. With the deepening of the study of obesity signaling pathways, a variety of potential therapeutic targets have been discovered, and some have advanced to the clinical stage, such as amylin, GDF15, and cheesophaginol.
amylin can reduce food intake and inhibit obesity symptoms. In addition to the cagrilintide, which is a composite preparation with semegglutide developed by Novo Nordisk, Eli Lilly registered the Phase I clinical study of the amylin analog LY3841136 at clinicaltrials.gov in March 2022, and Zealand Pharma also developed the same product ZP8396. The receptor of
growth differentiation factor 15 (GDF15) is GDNF family receptor alpha-like (GFRAL). Studies have found that inhibiting the GDF15-GFRAL pathway can control appetite and weight, so there are also company layouts, but they are all in early clinical practice, such as NN-9775 (NNC0165-1875) developed by Novo Nordisk and CinRx Pharma's CIN-109.In the development of
cheesypter (PYY) analog, Novo Nordisk and Eli Lilly each have a product, in which Novo Nordisk is using NNC0165-1875 with semegglutide in a phase II study to evaluate the efficacy of weight loss.
More potential products for obesity are still under development, such as THR-beta agonist ASC41 developed by Ganlai Pharmaceuticals, and Biomea Fusion's menin inhibitor BMF-219. Xinlitai cooperates to develop innovative obesity drugs by introducing AI technology from Alpha Molecular Technology. Novo Nordisk reached a cooperation with EraCal Therapeutics in January this year, hoping to discover potential new targets for appetite control in the drug discovery platform of zebrafish juvenile fish.
Treatment costs doubts
comes from a report released by the American Institute of Clinical and Economic Evaluation (ICER) in August that although GLP-1 agonists can have obvious weight loss effects, they are expensive and have poor cost-benefit analysis. This report compares the clinical effectiveness and value of semegglutide, liraglutide, Qsymia (pentamine/ topiramate ), and Contrave (bupropion/naltrexone) in the treatment of obesity.
According to ICER analysis, the weight loss effect of semegglutide and phentermine/topiramate was better than liraglutide and bupropion/naltrexone. In addition to weight loss, semegglutide and liraglutide can also bring cardiovascular benefits, such as improving blood sugar and blood pressure and , and semegglutide has the lowest drug discontinuation rate.
From the perspective of economic costs, both smegglutide and liraglutide are currently overpriced. The estimated net price of smegglutide is US$13,618 per year, which is only cost-effective if it drops to US$7,500 to US$9,800; the annual net price of liraglutide is US$11,760, and the cost-effective range is US$3,800 to US$4,800. The annual net prices of phentermine/topiramate and bupropion/naltrexone are $1,465 and $2,094 respectively, which are much cheaper than the two GLP-1 models.
ICER pointed out that semegglutide is more cost-effective, has higher efficacy and is less burden-free than liraglutide. It can be seen that although the current price of GLP-1 is relatively high, developing products with better weight loss results will bring better cost-effectiveness.
Currently, there is a lack of weight loss drugs in China. Phentermine/topiramate and bupropion/naltrexone are not available in China. The only approved weight loss drug is orlistat . Clinical results show that orlistat has adverse reactions such as diarrhea and oily stools, and the long-term cardiovascular risk is still unclear.
According to the survey results of the "Report on Nutrition and Chronic Diseases of Chinese Residents (2020)", more than half of the adult residents in my country suffer from overweight or obesity. The prevalence of overweight/obesity among children and adolescents under 6 years old and 6 to 17 years old has reached 10.4% and 19% respectively, and the prevalence is on the rise, and there is a large clinical need not met. The development of GLP-1 drugs will bring new therapeutic opportunities to obesity.
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