List of GLP-1 Receptor Agonists for Diabetes & Weight Loss

1. Huateng Pharma https://us.huatengsci.com List of GLP-1 Receptor Agonists for Diabetes & Weight Loss According to the latest Global Diabetes Map (10th edition) released by the International Diabetes Federation (IDF) in December 2021, the number of people aged 20 to 79 with diabetes worldwide was estimated at 537 million in 2021, with the number expected to grow to 700 million by 2045. Due to the large population of patients and the characteristics of long-term medication for chronic diseases, diabetes drugs have become the second largest market in the world. The number of type II diabetes patients accounted for about 95% of the total number of diabetes patients. Glucagon-like peptide-1 (GLP-1), as one of the important targets for the treatment of type 2 diabetes mellitus (T2DM), has obvious therapeutic effect, short half-life and easy to be cleared. With the dual effect of "diabetes" and "weight loss", the development of GLP-1 long-acting receptor agonists has become a research hotspot at home and abroad. GLP-1 And GLP-1 Receptor Agonists (GLP-1RA) GLP-1 (Glucagon-like peptide-1) is a peptide hormone encoded by the glucagon-like gene of human islet and secreted by intestinal L cells. It belongs to the incretin family, whose secretion is regulated by eating activities and has glucose-concentration-dependent hypoglycemic effect. Figure 1. Schematic diagram of GLP-1 structure characteristics GLP-1 inhibits glucagon secretion by acting on islet α cells, and islet α cells can increase GLP-1 production and secretion capacity. In addition, GLP-1 can

2. Huateng Pharma https://us.huatengsci.com slow gastric emptying, reduce appetite in patients and thus reduce body mass, control blood pressure, regulate blood lipids and protect cardiovascular function, and has a low risk of hypoglycemia. Figure 2. GLP-1 mechanism of action when blood sugar levels increase (Source: References[1]) Glucagon-like peptide 1 (GLP-1) is a polypeptide hormone mainly secreted by intestinal L cells. Its receptor GLP-1R is mainly expressed in islet β cells in the pancreas, and is also widely expressed in tissues such as stomach, small intestine, heart, kidney, lung and brain. GLP-1 binding to GLP-1R promotes β-cell glucose metabolism through mTOR-dependent HIF-1α activation. After GLP-1 binding, G protein conjugates GLP-1R receptors to activate adenylate cyclase (AC) and increase intracellular cAMP levels. Camp-mediated signaling promotes the mTOR pathway in beta cells, which induces HIF-1α translational activation. In the nucleus, HIF-1α drives the up-regulation of glycolysis gene transcription. Increased glycolytic enzyme pools in the cytoplasm allow for elevated glycolytic flux and glycolytic capacity, leading to faster ATP production and enhanced glucose-stimulated insulin secretion (Figure 3).

3. Huateng Pharma https://us.huatengsci.com Figure 3. Mechanism of action of GLP-1 binding to GLP-1R GLP-1 receptor agonists (GLP-1RA) have received extensive attention due to their advantages such as strong hypoglycemic effect, low risk of hypoglycemia (single agent), good weight loss effect and cardiovascular benefits. Looking at the global market, GLP-1RA has steadily increased its share in the market of hypoglycemic drugs. Currently, a number of drugs have been launched worldwide, which not only benefit type 2 diabetes patients, but also bring hope to many obesity patients. Listed Products of GLP-1 Receptor Agonists (GLP-1RA) At present, 9 GLP-1 receptor agonist hypoglycemic drugs have been approved for marketing in the world, namely: exenatide, liraglutide, Exenatide extended-release (exenatide ER), albiglutide, dulaglutide , lixisenatide,

4. Huateng Pharma https://us.huatengsci.com benaglutide, semaglutide, polyethylene glycol loxenatide injection and oral semaglutide. In addition, the FDA approved oral semaglutide in 2019, becoming the first oral dosage form of a GLP-1 receptor agonist. Table 1 GLP-1 analogues available in the market Exenatide Exenatide, sold under the brand name Byetta, was jointly developed by Amylin and Lily in the United States. The structural basis of Exenatide is Exendin-4 isolated from the saliva of the Gila monster, with a full length of 39 amino acids. Exenatide had 53% homology with GLP-1, had strong binding ability with GLP-1 receptor and was not easily degraded by DPP-4. Its plasma half-life was longer than GLP-1, reaching 100~120 min. Exenatide was administered by subcutaneous injection twice a day. It was approved by the US Food and Drug Administration (FDA) as a 2-line drug for T2DM patients in 2005, and was marketed in China in 2009. It is mainly used for T2DM patients with sulfonylurea, metformin and their combination, which are difficult to control blood glucose.

5. Huateng Pharma https://us.huatengsci.com The most common adverse reactions of exenatide are nausea and vomiting. Anti-exenatide antibodies were detected in 40%-60% of clinical patients. Hypoglycemic events have occurred with the combination of exenatide and insulin. Liraglutide Liraglutide, trade name Victoza, was developed by Novo Nordisk. The amino acid sequence of liraglutide is 97% homologous to GLP-1, and the lysine at position 26 is connected to a 16-carbon fatty acid, which not only enhances the resistance of liraglutide to the degradation of DPP-4, but also provides a slow release effect, extending the half-life to 10~14 h. It is administered once daily by subcutaneous injection. Liraglutide was approved by the FDA for marketing in the United States in 2010 and officially launched in China in 2011. On March 5, 2022, Novo Nordisk's world's first basal insulin GLP-1RA injection Xultophy® (Insulin Degludec/Liraglutide Injection) was officially launched in China. Since liraglutide is 97% homologous to natural GLP-1, the incidence of antibodies tested in the phase 3 clinical study was relatively low, with elevated antibody levels detected in less than 10% of individuals. Adverse effects included nausea and vomiting, excessive weight loss in patients with T2DM, and hypoglycemic events in combination with conventional hypoglycemic agents. Exenatide long-acting preparation Exenatide LAR, trade name Bydureon, is jointly developed by Amylin and Lily. In order to improve the medication compliance of diabetic patients, polylactic-co-glycolic acid (PLGA) was used to wrap exenatide drug, which has sustained-release effect, and the half-life is as long as 5-6 days. It is administered by subcutaneous injection once a week , can reduce the dosage and frequency of medication for patients. Exenatide long-acting preparations were launched in the United States in 2012 and officially launched in 2018 with the approval of the National Medical Products Administration (NMPA). In addition to nausea and vomiting, the most common adverse reactions of exenatide long-acting preparations also have a strong immunogenic reaction at the injection site, which is mainly caused by the rejection of polylactic acid-glycolic acid copolymer. Albiglutide Albiglutide, sold under the trade name Tanzeum, is developed by GlaxoSmithKline (GSK). Albiglutide is the second long-acting GLP-1 approved

6. Huateng Pharma https://us.huatengsci.com by the FDA in 2014 with 97% homology. The modified polypeptide can be combined with human albumin to enhance the resistance to DPP-4 and prolong the half-life to 5-6 days. It is administered by subcutaneous injection once a week. In clinical trials of Liraglutide (1.8 mg) and Albiglutide (50 mg), liraglutide was superior for reducing HbA1c, but was more likely to lose weight in patients. Albiglutide was associated with fewer hypoglycemic events and moderate weight loss, but Albiglutide based on fusion protein technology produced more antibodies due to its functional protein domain. Dulaglutide In 2014, the FDA approved the marketing of the long-acting GLP-1RAs dulaglutide (dulaglutide) developed by Eli Lilly and Company, with the trade name Trulicity. It was approved for listing in China in February 2019. Dulaglutide is covalently linked to human immunoglobulin IgG 4 heavy chain molecules to reduce immunogenicity, enhance water solubility, and avoid degradation by DPP-4. The half-life is 5 days, and it is administered by subcutaneous injection once a week. The most common side effects of dulaglutide are nausea, vomiting, and diarrhea. Like albiglutide, it has a lower probability of hypoglycemia and no significant weight loss. Similarly, because of the protein domain with certain functions, more antibodies appear in the body. Lixisenatide Lixisenatide was developed by Sanofi-Aventis in France. It was approved by the FDA under the trade name Adlyxin in 2016 and launched in China in January 2018. Among GLP-1 analogues, lixisenatide has a unique pharmacokinetics. It has a relatively short half-life, a strong ability to delay gastric emptying, and an affinity for GLP-1 receptor that is four times that of natural GLP-1. It is a once-daily subcutaneous injection. Compared with exenatide, lixisenatide is generally well tolerated, with a lower incidence of hypoglycemia, lower immune response at the injection site, and less side effects such as nausea and vomiting. Benaglutide Benaglutide (HYBR-014) is the world's first human amino acid sequence GLP-1 drug independently developed by BENEMAE. It was launched in China in December 2016. The drug has a short half-life and needs to be administered by subcutaneous injection three times a day. Therefore, patients need to receive multiple injections every day, which is quite painful for diabetic patients

7. Huateng Pharma https://us.huatengsci.com who already need frequent needle injections, and seriously affects patient compliance. A 3-month open-label trial investigated the weight loss and glycemic control effects of benaglutide in patients with T2DM. The results showed that the average body weight of 314 subjects was reduced by 10.05kg (P<0.0001), and the average HbA1c level was reduced by 2.87% (P<0.0001). The study showed that benaglutide can effectively treat T2DM, especially with Overweight or obese patients. Semaglutide Semaglutide (trade name Ozempic) is a new generation of long-acting GLP-1 receptor agonist developed by Novo Nordisk and approved by the US FDA on December 6, 2017. It is the seventh GLP-1RAs approved by the US FDA. Semaglutide has 94% homology with natural GLP-1, its amino acid backbone is connected with fatty acid side chains, and its half-life is extended to 165 h. It is administered by subcutaneous injection once a week. On September 20, 2019, the FDA approved the once-daily oral semaglutide (trade name Rybelsus) for marketing. Rybelsus is the world's first and only oral version of GLP-1 receptor agonist at present. This preparation uses 2-hydroxybenzamide as an absorbent to improve bioavailability while eliminating the inconvenience and psychological pain of injections. Semaglutide was more effective in dose-dependent reduction of glycosylated

8. Huateng Pharma https://us.huatengsci.com hemoglobin (HbA1c) and weight loss than liraglutide, according to clinical data presented at the annual conference of the European Diabetes Society. On December 3, 2021, semaglutide injection (commonly known as semaglutide) is the second GLP-1 new drug product launched by Novo Nordisk in China after liraglutide. It has shown good clinical advantages in hypoglycemia, weight loss, cardiovascular benefits, safety and other aspects. It has also shown better hypoglycemia and weight reduction effects in the "head-to-head" clinical trial with Dulaglutide, and is known as the best GLP-1 agonist in the world. In terms of hypoglycemia: HbA1c has been used as the gold standard in clinical evaluation of long-term blood glucose control. According to the 2018 consensus disclosure of EASDA, based on the existing clinical trial data, the hypoglycemic effects of the listed GLP-1 receptor agonists are ranked as follows: Semaglutide > dulaglutide ≈ liraglutide > albiglutide > lixisenatide > exenatide. Long-acting dosage forms have more advantages in blood sugar control due to their longer half-life and stable blood concentration. Figure 4 Hypoglycemic effect of oral semaglutide

9. Huateng Pharma https://us.huatengsci.com In terms of weight loss: According to the EASDA 2018 consensus disclosure, based on the existing clinical data, the weight loss effects of the marketed GLP-1 receptor agonists are ranked as follows: Semaglutide > liraglutide > dulaglutide > exenatide > lixisenatide > albiglutide. Overall, long-acting GLP-1 receptor agonists were more effective in reducing weight than short-acting formulations. Figure 5. Oral semaglutide for weight loss Polyethylene Glycol Losanatide Polyethylene glycol Loxanatide (PEX-168) is an original drug independently developed by Hansoh Pharma. On May 7, 2019, PEX-168 was approved by China's CFDA for marketing. PEX-168 is a novel hypoglycemic drug formed by modifying amino acids on the basis of the chemical structure of exenatide and modified with polyethylene glycol. Patients only need to inject it once a week for the blood sugar control of adults with type II diabetes mellitus. However, due to the widespread presence of anti-PEG antibodies and PEG complement activation in vivo, peglosanatide is limited to the suitable population. Future Directions For GLP-1 Receptor Agonists

10. Huateng Pharma https://us.huatengsci.com Judging from the current research and development trends, long-acting, oral dosage forms and multi-target receptor agonists are the key directions for the future development of GLP-1 receptor agonists. In 2021, the sales of Lilly's long-acting GLP-1 receptor agonist product dulaglutide were US$6.472 billion, up 49% from the previous year. From 2016 to 2020, the compound annual growth rate of long-acting GLP-1 agonists was as high as 50.1%, much higher than the 5.6% for short-acting GLP-1 agonists. It is worth mentioning that long-acting products will be more and more significant in the pulling effect of this kind of drug market, and will become mainstream drugs in the future. Currently, GLP-1 receptor agonist products on the market are all injectable forms. Compared with oral hypoglycemic drugs, patients' compliance with injectable drugs is relatively poor. The difficulty of GLP-1 receptor agonist oral products is that GLP-1 is easily degraded by enzymes in the gastrointestinal tract. The current product solution in the pipeline is to develop orally effective GLP-1 receptor agonists using different carrier technologies. Novo Nordisk achieved oral administration by combining semaglutide and SNAC, marking a milestone in the global oral product schedule as the first orally approved GLP-1 receptor agonist in the world. In the field of research and development of multi-target receptor agonist drugs, there are currently several multi-receptor agonists under research in the world that have entered the clinical stage. These drugs are synthesized by means of chimeric peptide or coupled peptide, such as GLP-1/GIP, GLP-1/GIP/ Glucagon and other multi-receptor agonists. According to the existing data results, the clinical effect of these new drugs in research is better than that of simple GLP-1 agonists in terms of hypoglycemia and weight loss. Conclusion In recent years, the diabetes drug market has continued to grow. Among the many updated and iterative products, drugs such as GLP-1 are definitely the most shining ones. From the earliest animal-derived exenatide to the human-derived GLP-1RA liraglutide, GLP-1RA has undergone short-acting, long-acting, weekly preparations and oral preparations, similar to the development of insulin analogs. From the FDA approval of the first GLP-1RA drug to the approval of oral semaglutide today, GLP-1RA has undergone several iterations. With the continuous progress of drug research and development, it has brought more effective, more convenient means of treatment. Type 2 diabetes is still a major

11. Huateng Pharma https://us.huatengsci.com challenge threatening the health of the global population, and we look forward to the discovery of more and better treatments. As a worldwide API & pharmaceutical intermediate and PEG derivatives supplier, Huateng Pharma supplies intermediates of Semaglutide and Liraglutide with capacities varying from gram to kilograms and multi tons. Semaglutide intermediates: CAS No. 166108-71-0, Fmoc-NH-PEG2-CH2COOH CAS No. 134978-97-5, NH2-PEG2-CH2COOH CAS No. 108466-89-3, Boc-NH-PEG2-CH2COOH CAS No. 134979-01-4, CH2COOH-PEG2-NH2.HCl CAS NO.1662688-20-1, Fmoc-L-Lys[Oct-(otBu)-Glu-(otBu)-AEEA-AEEA]-OH CAS NO.1118767-16-0, (S)-22-(Tert-butoxycarbonyl)-43,43-dimethyl-10,19,24,41-tetraoxo-3,6,12,15,4 2-pentaoxa-9,18,23-triazatetratetracontanoic acid CAS NO.1143516-05-5, 17-amino-10-oxo-3,6,12,15-tetraoxa-9-azaheptadecan-1-oic acid CAS NO.871-70-5, Octadecanedioic acid Liraglutide intermediates: CAS NO.204521-63-1, Pal-L-Gljavascript:void(0)-OtBu CAS NO.1491158-62-3, Fmoc-Lys(Pal-Glu-OtBu)-OH CAS NO.294855-91-7, Pal-Gljavascript:void(0)-OH CAS NO.536721-25-2, (S)-5-(tert-butoxy)-5-oxo-4-palmitamidopentanoic acid References: [1]. GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation [2]. DOYLE M E, EGAN J M. Mechanisms of action of glucagon-like peptide 1 in the pancreas [J]. Pharmacology & Therapeutics, 2007, 113(3): 546-593. [3]. GROMADA J, HOLST J J, RORSMAN P.Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1 [J]. Pflügers Archiv, 1998, 435(5): 583-594. [4]. LOVSHIN J A. Glucagon-like peptide-1 receptor agonists: a class update for treating type 2 diabetes [J]. Canadian Journal of Diabetes, 2017, 41(5): 524-535. [5]. https://www.tiprpress.com/ywpjyj/article/abstract/20200337 [6]. Julian M. Yabut and Daniel J. Drucker, Glucagon-like Peptide-1 Receptor-based Therapeutics for Metabolic Liver Disease, Endocrine Reviews, 2023, 44, 14–32.

12. Huateng Pharma https://us.huatengsci.com Related articles: [1]. Semaglutide: A Star Product In The Field of Hypoglycemic And Weight Loss [2]. Overview of Diabetes Treatment [3]. Emerging Role of Dual GLP-1 Receptor Agonists