'Weight loss needle' is coming to China soon! Why is Semaglutide the best GLP-1 student?

Recently, the Center for Drug Evaluation of the National Medical Products Administration showed that Novo Nordisk's semaglutide has been officially accepted for weight loss indications. With the excellent performance of GLP-1 drugs this year, Novo Nordisk's market capitalization continues to reach new highs, second only to Eli Lilly and Johnson & Johnson. Semaglutide is undoubtedly the pearl in the crown of Novo Nordisk.

GLP-1, a peptide hormone derived from proglucagon, is mainly produced in the gut and brain stem. When GLP-1R (GLP-1 receptor) is activated in insulin β cells, it can stimulate insulin secretion, inhibit the release of glucagon by insulin α cells, and delay emptying. Through central appetite control, it can reduce food intake to reduce blood glucose and lose weight.

Figure 1 Mechanism of action of GLP-1

Photo credit: Novo Nordisk's 2023 quarterly report

Semaglutide was approved in multiple dosage forms and specifications

Semaglutide is the second GLP-1R agonist to be marketed by Novo Norad after liraglutide, and the second GLP-1R agonist to obtain dual indications for obesity and type 2 diabetes mellitus (T2DM) in the world.

The molecular structure of GLP-1 was 94% identical to that of native GLP-1 with only three modifications. The first modification was the substitution of Lys to Arg at position 34. The second is the addition of an 18-carbon fatty acid to Lys 26, which enhances the binding ability of the molecule to albumin and prolongs the half-life of semaglutide in vivo by preventing its enzymatic degradation and delaying its renal metabolism. The third position is at position 8, where Ala is replaced by α-Aib, which prolongs the half-life by hindering DPP-4 degradation of the GLP-1R agonist.

Figure 2 Molecular structure of semaglutide

Image source: Reference 3

Semaglutide is currently approved in two formulations: injectable (Ozempic and Wegovy) and oral (Rybelsus).

In December 2017, the US FDA approved semaglutide injection (Ozempic) for the treatment of T2DM. In 2021, the FDA approved Wegovy for weight management, and its indication for diabetes was approved in China in April of the same year. Rybelsus, an oral formulation, received FDA approval in 2019 for the treatment of T2DM.

The sales of semaglutide hypoglycemic injection (Ozempic), semaglutide tablets (Rybelsus), and semaglutide weight loss injection (Wegovy) in 2022 were 59.75 billion Dan Macron ($8.439 billion), 11.299 billion Dan Macron ($1.569 billion) and 6.188 billion Dan Macron, respectively Lang ($874 million).

GLP-1 has great potential in two fields of diabetes and weight loss

Orlistat is the only weight-loss drug listed in China, but it has problems such as oil leakage and is generally effective.

Although the current approved indication for semaglutide in China is diabetes, it is also common for semaglutide to be used off-label for weight loss. According to CITIC Securities, the market size of GLP-1R agonist weight loss drugs in China is expected to reach about 38.3 billion yuan by 2030. Although insulin has experienced specialized procurement and prices have dropped significantly, it is still a large market, and China's anti-diabetes market is expected to grow to 116.1 billion yuan by 2025, according to Frost & Sullivan.

In the field of T2DM treatment, hypoglycemic drugs are mainly divided into eight categories: metformin, SGLT-2 inhibitors, GLP-1R agonists, DPP-4 inhibitors, thiazolidinediones, sulfonylureas and insulin. GLP-1R agonists and insulin had the best glucose-lowering effect, both of which were in the highly effective range, and GLP-1R agonists did not have the potential hypoglycemic risk similar to insulin. In terms of weight change, GLP-1R agonists were more effective. In addition, GLP-1R agonists have clinical benefits with respect to cardiovascular and renal function.

Figure 3 Comparison of mainstream hypoglycemic drugs in the market with GLP-1

Photo credit: Novo Nordisk's 2023 quarterly report

As the top GLP-1 product, semaglutide has excellent clinical performance in the two indications of hypoglycemic and weight loss, and a number of head-to-head trials have verified its leading position. Novo Nordisk is also actively expanding the application of semaglutide in the treatment of non-alcoholic steatitis, Alzheimer's disease and other fields.

Multiple large head-to-head clinical achievements

Semaglutide is the preferred GLP-1 product

According to the results of the SUSTAIN large-scale clinical trial of semaglutide injection (Ozempic) published by Novo Norad, semaglutide injection is effective in the treatment of T2DM compared with the control drugs (sitagliptin, exenatide microspheres, insulin glargine, and duraglutide, etc.).

Dulaglutide is one of the most widely used antidiabetic drugs. The results of SUSTAIN 7 study showed that 1.0mg semaglutide reduced HbA1c by 1.8% after 40 weeks, which was significantly better than the control drug (1.0mg dulaglutide). In the low-dose group, semaglutide (0.5mg) was also significantly better than the control drug (0.75mg) in reducing HbA1c. After 40 weeks of treatment, semaglutide reduced fasting blood glucose by 2.8mmol/L, which was also significantly better than the control drug.

According to the American Diabetes Association, the monthly cost of GLP-1 drugs ranges from US $727 to US $975 based on the national average drug purchase cost. Federal/state medical insurance can cover the cost of GLP-1 drugs, and patients with commercial insurance can receive Ozempic for 3 months at a minimum of US $25.

Figure 4 Results of semaglutide SUSTAIN studies

Photo credit: Novo Nordisk 2023 quarterly report

Semaglutide (Wegovy, 2.4mg) was associated with a weight loss of 16.9% to 18.2% among treated patients in the weight-loss STEP study. In the STEP 8 head-to-head study of liraglutide, also GLP-1, patients in the Wegovy group lost 17.1% of their body weight, while Saxenda lost only 6.6%.

Figure 5 Results of the semaglutide STEP study

Photo credit: Novo Nordisk 2023 quarterly report

In the first quarter, Ozempic generated revenues of DKK 19.64 billion, up 59 per cent from a year earlier, while Wegovy generated revenues of DKK 4.563 billion, up 211 per cent. In April this year, Novo Nordisk raised its 2023 full-year revenue and profit expectations, mainly due to the strong demand for semaglutide injection products and the readiness of the second manufacturer on the supply side. It is expected that in 2023, Novo Nordisk's revenue will grow by 24%-30% and profit will grow by 28%-34%.

The semaglutide patent does not expire until 2031, and the product will provide continuous cash flow for Novo Nordisk in the future.

Rybelsus, an oral once-daily form of semaglutide, was approved by the FDA in September 2019 for the treatment of T2DM, becoming the world's first oral GLP-1 product.

"In a head-to-head study of Rybelsus versus placebo, empagliflozin, sitagliptin, and liraglutide in the large global PIONEER program, Rybelsus showed statistically significant reductions in HbA1c and 4.3 kg of weight loss after 52 weeks of treatment." Rybelsus has a good safety and tolerability profile, and the most common adverse effect was mild to moderate nausea, which gradually alleviated over time. Oral semaglutide is in phase 3 clinical studies of two high doses of 25 mg and 50mg for the treatment of T2DM.

On March 24, Novo Nordisk presented PIONEER PLUS phase 3 trial data showing that oral semaglutide 25mg and 50mg were statistically superior to oral semaglutide 14mg with respect to HbA1c and body weight. With regard to glycemic control, patients treated with 25mg and 50mg semaglutide had reductions in HbA1c of 1.9 and 2.2 percentage points, respectively, and 1.5 percentage points compared with 14mg semaglutide. With regard to weight loss, patients treated with 25mg and 50mg semaglutide lost 7kg and 9.2kg, respectively. Weight loss in the 14-mg group was only 4.5kg.

Subsequently, on May 22, Novo Nordisk presented data from the phase 3a OASIS 1 weight-loss study of oral semaglutide, a 50-mg tablet, in which patients in the semaglutide 50-mg group lost 17.4% of body weight, as compared with 1.8% in the placebo group. It is anticipated that marketing applications for semaglutide 50mg tablets will be filed in the United States and European Union this year.

Figure 6 Results of the PIONEER study of oral semaglutide

Photo credit: Novo Nordisk 2023 quarterly report

Eli Lilly's telpotide has shown excellent performance in the field of glucose control and weight loss after its introduction, which has put pressure on Novo Nordisk.

According to the previous data published by Eli Lilly, the weight loss of 15mg telpotide injection in 72 weeks was 20.9%, which was better than that of 2.4mg semaglutide injection in 68 weeks, which was 17%. In order to further establish the advantage, Eli Lilly registered a head-to-head clinical trial of telpotide and semaglutide on weight loss this year. The OASIS 1 findings can come as some relief to Novo Nordisk. But now the market demand is not met, limit semaglutide volume is capacity.

Figure 7 Growth in prescriptions for Rybelsus, an oral semaglutide formulation, in North America

Photo source: Industrial Securities

Huadong Medicine and Cinda lead domestic GLP-1 research and development

There are 9 GLP-1R agonists marketed in China, namely exenatide, lixisenatide, liraglutide, exenatide microspheres, duraglutide, semaglutide, telpotide, benaglutide and polyethylene glycol losenatide. Among them, benaglutide and polyethylene glycol losenatide are domestic GLP-1R agonists, and the rest are imported products.

The research and development of GLP-1 drugs in China are mainly focused on liraglutide and semaglutide-like drugs, and Huadong Medicine and Cinda Bioscience are in the leading position.

The patent of liraglutide in China has expired. The patent of semaglutide in China will expire in 2026, and the core patent of semaglutide has been judged invalid by the State Intellectual Property Office. Novo Nordisk has appealed the judgment to the Beijing Knowledge Industry Court. Assuming that the original judgment is maintained, the domestic generic semaglutide is expected to be rapidly marketed in 1-2 years.

In March, Huadong Medicine's liraglutide injection was approved for marketing. In addition to liraglutide injection, Huadong Medicine also has a number of investigational pipeline in the field of GLP-1 drugs, including small-molecule oral GLP-1R agonists, GLP-1R/GIPR dual-target agonists, GLP-1R/GCGR/FGF21R multiple agonists, etc.

Cindar Bio's IBI362 is the first dual-target drug (GLP-1/GCGR) to enter phase 3 in China. This drug is a gastrin regulatory analogue, which has dual effects of activating GLP-1 receptor and glucagon receptor (GCGR). The drug is a new generation drug for regulating glucose metabolism introduced by Cinda from Eli Lilly, and the company has the development and commercialization rights in Greater China. The phase 2 clinical study of IBI362 has been completed and all key endpoints have been met. Currently, all have entered clinical phase 3, and IBI362 is expected to become the first domestic dual-target GLP drug.

Semaglutide set off 10 billion weight loss market battle has begun, who will pull out the first let us wait and see!