There is no doubt that this is the era of GLP-1.

Recently, in less than a month, three GLP-1 transactions were concluded one after another, involving an amount exceeding US$4.4 billion. First, Merck introduced the small molecule GLP-1RA HS-10535 from Hansoh Pharmaceuticals, and then Jixing Pharmaceutical introduced the global (except Greater China) development and commercialization rights of the oral small molecule GLP-1RA CX11 from Wingtech Pharmaceuticals. Recently, Verdiva Bio, an overseas Biotech company, has introduced the rights to once-weekly oral inoglutide from Xianweida Biotech.

Among these transactions, a significant trend has attracted attention-the oral dosage form of GLP-1 drugs has become the focus of competition among pharmaceutical companies. Both emerging biotechnology companies and established pharmaceutical giants are all focusing their R&D resources on oral GLP-1 drugs, and a fierce competition around oral dosage forms has begun.

The advantages are fully demonstrated

. Currently, the mainstream GLP-1 drugs are mainly injections. The use of injection drugs is restricted by many conditions such as time and location, resulting in poor medication compliance. The oral dosage form is more convenient to take, greatly improving patient compliance.

From the perspective of production costs, the production process of macromolecular peptide drugs is relatively complex, requiring the use of biological fermentation technology, complex protein purification processes, and strict cold chain transportation and storage conditions, from the screening of raw materials, optimization of fermentation conditions, and protein synthesis. Extraction and refining, as well as packaging and transportation of finished products, each step requires high costs.

As the leading companies of GLP-1 drugs, Novo Nordisk and Eli Lilly have been plagued by production and supply restrictions. In order to solve the supply problem of GLP-1 drugs, Novo Nordisk spent a lot of money to acquire production plants and built its own sites to improve its hematopoietic capacity. In February 2024, Novo Nordisk acquired CDMO giant Catalent for US$16.5 billion. As part of the deal, Novo Nordisk will acquire three filling plants in Italy, Belgium and Indiana in the United States for US$11 billion. Eli Lilly's Tilpotide has been on the FDA's shortage list of drugs since it was launched two years ago. Especially after the weight loss indication was approved, the supply exceeded demand. It was not until December 2024 that the FDA confirmed the shortage of Lilly's Tilpotide. be resolved.

On the other hand, small molecule GLP-1 drugs can be prepared on a large scale through chemical synthesis. The production process is mature and the cost is relatively low, which can greatly improve the production and supply capabilities of pharmaceutical companies. This huge cost advantage gives small molecule GLP-1 drugs a powerful "price weapon" in market competition, which is expected to attract more patients to benefit from GLP-1 drug treatment, thereby having a profound impact on the entire GLP-1 drug market structure. influence and reshape the competitive situation of the market.

Judging from clinical data, clinical research data from multiple pharmaceutical companies provide solid support for the effectiveness of oral GLP-1 drugs.

Currently, there is only one oral GLP-1RA approved, Novo Nordisk’s semaglutide tablets. In January 2024, semaglutide tablets were launched in China for the treatment of diabetes. Novo Nordisk's semaglutide tablets, prepared with the innovative technology of "SNAC absorption enhancer", increase the bioavailability of the semaglutide molecule by approximately 100 times. Oral semaglutide has also demonstrated good weight loss effects. The results of the OASIS 1 study showed that oral administration of 50 mg of semaglutide per day can significantly reduce the weight of overweight or obese patients. After 68 weeks of treatment, the average weight of patients decreased by 15.1%, and the proportion of patients who achieved weight loss of ≥5% was as high as 85%.

Eli Lilly and Company's small molecule GLP-1RA Orforglipron demonstrated statistically significant dose-dependent weight loss at all doses in the primary endpoint assessment at Week 26 in obese patients in a Phase 2 clinical trial of Orforglipron. The range was 8.6% to 12.6%, and only 2.0% in the placebo group. After 36 weeks of treatment, subjects at all doses continued to lose weight, with weight loss ranging from 9.4% to 14.7%, while the placebo group only lost 2.3%. The hypoglycemic effect of Orforglipron is also significant. After 26 weeks of treatment, the average decrease in glycated hemoglobin (HbA1c) of patients in the 45 mg group reached 2.1%.

Common Problems

Despite this, the development of small molecule GLP-1 drugs is not a smooth road, and safety issues have always been a common problem.

In 2024, Pfizer decided to abandon the continued development of the GLP-1 small molecule Lotiglipron. The core reason was that its safety issues encountered huge challenges. In the phase 2 clinical trial of this drug, subjects experienced an increase in transaminase. Abnormal fluctuations in this key indicator are undoubtedly a serious warning for liver safety. Then in December 2024, the results of the Phase 2b clinical trial of another GLP-1 small molecule Danuglipron were announced. Although the drug met the primary endpoint in terms of weight loss, up to 73% of patients experienced nausea and 47% of patients experienced nausea. Vomiting and diarrhea occurred in 25% of patients. Compared with the placebo group, more than 50% of the treatment group discontinued treatment, which is even more staggering. Danuglipron's huge flaws in safety and tolerability also forced Pfizer to adjust its research and development strategy, and also made its peers deeply aware of the seriousness of the safety issue.

Compared with peptide GLP-1 drugs, small molecule drugs are usually designed and synthesized artificially from scratch and are not endogenous substances. The metabolic process of small molecules in the complex environment of the human body and their interactions with various receptors are difficult to accurately predict. This makes small molecule GLP-1 drugs more prone to safety issues. Taking liver toxicity as an example, some small molecule GLP-1 drugs may interfere with the normal metabolic pathways of the liver and affect the function of liver cells. In the gastrointestinal tract, due to the particularity of the small molecule structure, it may over-stimulate gastrointestinal receptors, causing nausea, vomiting, diarrhea and other adverse reactions, seriously affecting patients' medication compliance. These uncertainties constitute its security obstacles.

Faced with the safety dilemma of small molecule GLP-1 drugs, the industry is also looking for a way to break the situation. For example, design multi-target drugs with GLP-1 as the core, gastric inhibitory peptide receptor (GIPR), glucagon receptor (GCGR), amylin, fibroblast growth factor 21 (FGF21R), etc. The target is the primary target in combination with GLP-1. Compared with a single GLP-1RA, multi-target drugs can achieve higher therapeutic potential and are more effective in glucose control and weight loss.

Viking Therapeutics’ VK-2735 and Hansoh Pharmaceuticals’ HS-20094 are both GLP-1R/GIPR dual-target agonists. Phase 1 clinical data of VK-2735 tablets show that after 28 days of treatment (dose up to 100 mg), the average body weight of subjects in the VK2735 treatment group decreased in a dose-dependent manner from baseline, with a decrease of up to 8.2%. Meanwhile, oral VK2735 also demonstrated an encouraging safety and tolerability profile, with the majority (99%) of observed treatment-emergent adverse events being mild or moderate, with the majority (90%) reported as mild. At present, the oral tablet has started a phase 2 clinical study for obesity.

In addition, some companies are also trying to use artificial intelligence to empower GLP-1 small molecule drugs, using computer-aided drug design to optimize the molecular structure, minimize off-target effects, and reduce potential damage to non-target organs. The MDR-001 project is one of the representatives. This variety is an oral GLP-1RA small molecule manufactured by DeRui Intelligent Pharmaceuticals with the help of an AI platform. It has entered Phase 2b clinical research for obesity.

Giants compete

in the field of oral small molecule GLP-1 drugs, a field full of potential, and a fierce R&D competition has begun. According to public data, as of now, there are more than ten small molecule GLP-1 drugs for weight loss indications that have entered the clinical stage around the world, and giants such as AstraZeneca and Eli Lilly have entered the market.

Eli Lilly is one of the leaders in the GLP-1 track, and its small molecule GLP-1 drug Orforglipron is leading the way and is currently in phase 3 clinical research. This drug can bind to multiple regions of the GLP-1R receptor. This special combination brings potentially better activation of adenylyl cyclase and subsequent physiological effects. Currently, Orforglipron has launched multiple Phase 3 clinical trials and is expected to become the first commercialized oral GLP-1 small molecule drug for weight loss.

Roche spent US$3.1 billion to acquire Carmot Therapeutics in December 2023, strongly entering the GLP-1 track. Phase 1 clinical trial data of its oral small molecule GLP-1 receptor agonist CT-996 showed that after four weeks of treatment, the weight of the CT-996 treatment group significantly decreased by 7.3%, while the placebo group lost only 1.2% of their weight. Pharmacokinetic studies strongly support its once-daily oral dosing regimen, and its safety and tolerability are good, with no unexpected risk signals.

After experiencing setbacks in the development of products such as the GCGR/GLP-1R dual agonist Cotadutide, AstraZeneca turned to focusing its resources on developing the drug AZD9550 with the same mechanism. On the other hand, it entered into a cooperation with Chengyi Biotech to introduce oral GLP-1R agonist ECC5004 to explore the therapeutic potential of this GLP-1 drug in the cardiovascular field. AstraZeneca paid an upfront payment of US$185 million, a milestone amount of US$1.825 billion, and a certain percentage of sales. According to the latest results of a phase 1 clinical trial of AZD5004 in obese patients with type 2 diabetes released by AstraZeneca, whether patients take AZD5004 with food or not will not affect its pharmacokinetic characteristics. Among patients treated with AZD5004 at a dose of 50 mg, body weight decreased by 5.8% compared to baseline after 4 weeks. At the same time, the patient's fasting blood sugar and other indicators also declined. This once-daily GLP-1 small molecule drug under development is expected to achieve a rapid breakthrough with the help of AstraZeneca's strong R&D and commercialization capabilities.
Looking at the global small molecule GLP-1 drug track, most of the layout comes from domestic pharmaceutical companies. Hengrui Medicine's HRS-7535 is in Phase 3 clinical trials, Huadong Medicine's oral weight loss drug HDM1002 tablets and Xinlitai's SAL0112 are in Phase 2 clinical trials, and Hiseco and Poinsettia are in Phase 1 clinical trials.

Ascletis' ASC30 is the first and only small molecule GLP-1 receptor agonist that can be injected subcutaneously once a month or taken orally once a day for the treatment of obesity. The top-line data of the Phase 1 clinical trial in the United States is expected to be announced in the first quarter of 2025.

MDR-001 is an oral small GLP-1RA pipeline designed by Deruizhi Pharmaceuticals using its self-developed AI pharmaceutical platform. MDR-001 retains the pancreatic cell repair and protection function brought about by β-arrestin recruitment, and avoids the limited insulin secretion and mediated endocytic desensitization brought about by β-arrestin 1 recruitment. Phase 2b clinical trials are currently underway. After taking MDR-001 tablets for 12 weeks, the average weight loss of the MDR-001 group was 9.0% (placebo 2.1%). At the same time, MDR-001 showed good safety and tolerability, and no serious adverse events occurred.

In recent years, many domestic GLP-1 small molecule oral drugs have joined the global battle through authorization.

On January 10, 2025, Verdiva was granted the exclusive right to develop, produce and commercialize a product portfolio including the once-weekly oral GLP-1 receptor agonist oral enoglutide worldwide outside of Greater China and South Korea.

On December 23, 2024, Jixing Pharmaceutical announced the introduction of global (except Greater China) development and commercialization rights of oral small molecule GLP-1 RA CX11 from Wingtech Pharmaceuticals. According to public information, CX11 has shown very significant efficacy in weight loss, and has good safety and tolerability, and has the potential to become the best oral small molecule GLP-1RA in its class. Currently, a registration phase 3 clinical study for patients with obesity and overweight has been launched in China.

On December 18, 2024, Merck and Hansoh Pharmaceuticals announced that the two parties have reached a global exclusive licensing agreement for the preclinical oral small molecule GLP-1RA HS-10535 under development. Hansoh Pharmaceuticals will receive an initial payment of US$112 million, a milestone payment of up to US$1.9 billion, and royalties.

In May 2024, Hengrui Medicine, through NewCo, licensed the company's exclusive rights to develop, produce and commercialize GLP-1 innovative drugs HRS-7535 (oral small molecule GLP-1RA), HRS9531, and HRS-4729 with independent intellectual property rights worldwide except Greater China to Hercules, a US company. HRS-7535 tablets are currently undergoing phase 3 clinical studies for obesity.

In recent years, the GLP-1 drug market has shown explosive growth. According to professional organizations, by 2030, the global GLP-1 drug market is expected to exceed the $100 billion mark, becoming one of the most promising "golden tracks" in the pharmaceutical field.

The field of oral GLP-1 drug research and development is full of unlimited opportunities, but also faces many challenges. With the continued rise in the incidence of metabolic diseases such as obesity and diabetes worldwide, people's demand for efficient and convenient therapeutic drugs has become more urgent, which provides a broad market space for oral GLP-1 drugs. As more pharmaceutical companies invest in the research and development of oral GLP-1 drugs, the share of this market segment is expected to further expand.

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