Emerging Role of Dual GLP-1 Receptor Agonists

1. Huateng Pharma https://us.huatengsci.com Emerging Role of Dual GLP-1 Receptor Agonists The management of diabetes has changed dramatically during the past hundred years. Biguanides, insulins, sulfonylureas, glycosidase inhibitors, thiazolidinediones, glinides, DPP-IV inhibitors, and SGLT-2 inhibitors are all competing in this field. Today, Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are one of the most attractive option for the treatment diabetes because they effectively lower A1C and weight while having a low risk of hypoglycemia. To date, GLP-1RAs have accounted for 12% of the glucose-lowering drug market and are maintaining a high growth trend. Development of GLP-1RA Since the first GLP-1RA, exenatide, was approved in 2005, more than 10 products (by active ingredient/combination) have been marketed worldwide. At present, there are three blockbuster products, liraglutide, dulaglutide and semaglutide (with annual sales of USD 5 billion). Figure 1. Listed GLP-1RA drugs Liraglutide, approved by the FDA in 2010 under the brand name Victoza®, has surpassed exenatide in sales in the first two years of marketing due to its

2. Huateng Pharma https://us.huatengsci.com excellent efficacy and lower adverse effects. Liraglutide has occupied the top spot in the market of GLP-1 RAs for nearly a decade, with sales peaking at $5 billion in the 10th year after launch (2019). Dulaglutide was launched by Eli Lilly in 2014 and proved non-inferior to liraglutide in a type 2 diabetes head-to-head trial. Thanks to the reduced frequency of dosing (once a week), dulaglutide sales climbed rapidly, topping $5 billion in the sixth year after launch (2020). But the good times did not last long, as semaglutide sales surpassed dulaglutide in the first half of 2022. Semaglutide was launched in 2017 and beat dulaglutide in a phase 3 head-to-head superiority trial, demonstrating excellent clinical glucose-lowering effects. After the approval of the injectable Ozempi, the oral tablet Rybelsus and the weight reduction drug Wegovy have been launched successively. Semaglutide has exceeded USD 5 billion in only 3 years of market launch and will sprint for USD 10 billion in 2022, and the future market ceiling will be higher than the first two drugs. Figure 2. 2012 to 2022H1 sales of three blockbuster GLP-1RA drugs GLP-1RA has continued to iterate on the demand for improved adherence, with essentially every new generation of GLP-1 drugs achieving a comprehensive overtake of the previous generation. The first marketed GLP-1RA drug, exenatide, began to decline in sales in the second year of liraglutide's launch, with peak sales ending at $797 million in 2009. The same was true for the first long-acting weekly formulation, exenatide microspheres, with sales peaking at $580 million three years after launch. The market performance was even more average for lixisenatide launched by Sanofi (2013) and albiglutide launched by GSK (2014, withdrawn from the market in 2018).

3. Huateng Pharma https://us.huatengsci.com The above products are not as effective in lowering glucose as earlier products or have greater side effects, so even though they had a lead at the time of commercialization, they were eventually replaced by later-marketed drugs with better efficacy. Emerging Dual GLP-1 Receptor Agonists In the face of fierce competition from single-target drugs, Novo Nordisk and Eli Lilly introduced GLP-1/GIP receptor dual agonists to the clinic in 2014 and 2016, respectively. And in May 2022, Eli Lilly received FDA approval for its dual GLP-1R/GIPR agonist Tirzepatide (Mounjaro), becoming another blockbuster drug in the glucose-lowering field. Figure 3. Dual GLP-1 RAs under investigation GLP-1R/GIPR Tirzepatide has achieved rapid sales growth since its launch. According to Eli Lilly's third-quarter financial report, Mounjaro generated $187 million in revenue in the third quarter and $200 million in cumulative revenue since its launch. Mounjaro is expected to be Eli Lilly's new ace in the hole against Novo Nordisk's semaglutide. Mounjaro sales are expected to reach $4.7 billion in 2026, according to an analysis of data from research firm Refinitiv.

4. Huateng Pharma https://us.huatengsci.com Tirzepatide not only showed better results in glucose lowering and weight loss than semaglutide in a phase 3 head-to-head study in type 2 diabetes (SURPASS-2), but also achieved an average weight loss of 22.4% in clinical phase 3 (SURMOUNT-1), making it the first drug to achieve an average weight loss of more than 20% in clinical phase 3 (the average weight loss of semaglutide in the clinic was around 15%). Eli Lilly has planned to file a marketing application for tirzepatide for weight loss in the fourth quarter of 2022. Figure 4. Comparison of glucose-lowering and weight-loss effects of Tirzepatide and semaglutide in the SURPASS-2 head-to-head trial (Source: Reference 4)

5. Huateng Pharma https://us.huatengsci.com GLP-1R/GCGR As the competition for type 2 diabetes drugs is too fierce, nonalcoholic steatohepatitis (NASH) has become a priority choice for late-stage clinical dual GLP-1/GCG receptor agonists, such as the development programs of AstraZeneca, Merck Sharp & Dohme (Efinopegdutide), and Boehringer Ingelheim. In the Phase IIb clinical results published in 2021, AstraZeneca's Cotadutide was compared with liraglutide and had similar glucose-lowering and weight-loss effects in the clinical setting (except for the 500ug weight-loss effect). Such data is disappointing when dual agonists are compared to older drugs marketed 10 years ago, not to mention benchmarking against a host of newer drugs, such as simeglutide. Figure 5. Comparison of glucose-lowering and weight-loss effects of Cotadutide and liraglutide (Source: Reference 5) Thankfully, patients showed significant improvement in liver parameters AST and ALT levels and liver fibrosis after Cotadutide treatment and contrasted differently with liraglutide. As a result, AstraZeneca also initiated a phase III clinical study of Cotadutide for NASH in May 2022. It should be noted that in this study there was a significant increase in TRAEs (46%-61% vs. 22.7%) and discontinuation rates (13%-21% vs. 1.8%) after Cotadutide treatment compared to liraglutide.

6. Huateng Pharma https://us.huatengsci.com Figure 6. Clinical improvement of liver indices with Cotadutide versus liraglutide (Source: Reference 5) Conclusion The long-acting and oral administration of GLP-1 drugs are the two major achievements in the field of glucose lowering, and Professor Daniel Drucker, one of the founders and outstanding leaders in the field of GLP-1 research, has optimistically predicted that in the near future, GLP-1 drugs will replace insulin as the main line of diabetes treatment. In the weight loss market, GLP-1 drugs, which can be used to lose weight with a single injection, have even more room for imagination. Huateng Pharma is known worldwide for a variety of pharmaceutical intermediates used in research and development. We can provide antidiabetic drug intermediates such as Canagliflozin intermediates, Dapagliflozin intermediates and Empagliflozin intermediates for commercial scale production. We can also supply Alogliptin intermediates, Linagliptin intermediates, Liraglutide intermediates, Semaglutide intermediates and Sitagliptin intermediates which are on R&D stage.

7. Huateng Pharma https://us.huatengsci.com References: 1. Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018;18:3-14. doi:10.1016/j.molmet.2018.09.009 2. Frias JP, Bastyr EJ 3rd, Vignati L, et al. The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes. Cell Metab. 2017;26(2):343-352.e2. doi:10.1016/j.cmet.2017.07.011 3. Campbell JE. Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms. Mol Metab. 2021;46:101139. doi:10.1016/j.molmet.2020.101139 4. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515. doi:10.1056/NEJMoa2107519 5. Nahra R, Wang T, Gadde KM, et al. Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes: A 54-Week Randomized Phase 2b Study [published correction appears in Diabetes Care. 2022 Oct 03;:]. Diabetes Care. 2021;44(6):1433-1442. doi:10.2337/dc20-2151 Related Articles Anti-Obesity Drugs: History And Development Ongoing Investigation of Weight Loss Therapies: 3 Positive Trends Overview of Diabetes Treatment Strategies