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Slow-release dual agonist therapy can treat hyperglycemia and obesity

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China has the largest number of diabetic patients in the world, followed by India and the United States. According to the latest statistics, my country currently has 116.4 million diabetic patients. One out of every four diabetic patients in the world comes from China, and this trend is expected to continue until 2045. Currently, it is estimated that 463 million people aged 20 to 79 have diabetes worldwide, and most of them are type 2 diabetes, which is characterized by insulin resistance and impaired ability to maintain glucose homeostasis. Treatment usually starts with oral hypoglycemic drugs, but these drugs can only have a temporary effect and are often accompanied by risks such as weight gain, which increase the risk of many common cancers, including liver cancer, pancreatic cancer, endometrial cancer, and colorectal cancer. , Breast cancer, etc. Therefore, there is an urgent need to develop drugs or drug combinations that can control blood sugar to the greatest extent while promoting weight loss.


Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are a class of incretins that can enhance glucose-stimulated insulin secretion and reduce food intake. Such drugs can lower fasting blood sugar levels and keep blood sugar under long-term control, and can cause mild to moderate weight loss in most patients. Compared with the blood sugar levels that the previous traditional medicines can achieve, more patients can reach their blood sugar goals. Although they have a unique mechanism of action and reliable clinical records, GLP-1RA cannot fully achieve long-term blood glucose control in T2D patients, and the weight loss caused by these drugs rarely corrects obesity. Give more weight to increase weight loss. High doses are also usually limited by gastrointestinal side effects.

GLP-1 multi-activation therapy is a treatment strategy that has attracted great interest recently. Its goal is to promote weight loss and improve blood sugar control, not just what GLP-1RA provides. Peptides with balance antagonism against GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) have been shown to enhance weight loss and blood sugar control, when the thermogenic effect of glucagon agonists is integrated into multi-agonist peptides At this time, the weight loss effect will be further enhanced.

Researchers believe that FGF21 can be a suitable candidate for pairing with GLP-1. FGF21 has recently been identified as an important metabolic hormone that targets the liver, pancreas and adipose tissue to regulate insulin sensitivity, energy expenditure and lipid metabolism. FGF21 analogs are being sought as drug candidates for the treatment of T2D and obesity and non-alcoholic steatohepatitis. The emerging human clinical trial data seems promising. In addition, the FGF21 component can not only localize the blood sugar effect on the pancreas, but also further improve blood sugar control by acting on the surrounding tissues to increase insulin sensitivity.

To this end, researchers tried to design a drug that can simultaneously have GLP-1 and FGF21 receptor agonistic effects and develop a simple and innovative strategy that combines elastin-like peptides (ELP) as GLP-1 and FGF21 The flexible connecting body between. In mouse models of obesity and hyperglycemia, dual agonist drugs can strongly improve metabolic parameters, restore blood sugar control and inhibit weight gain. At the same time, ELP reduces the required dosing frequency to once a week, solving one of the main obstacles to the development of GLP-1 and FGF21 as drugs (their plasma half-lives are short, minutes and hours, respectively). Recently, the research results were published in “Science Advances”.

GLP1-ELP and ELP-FGF21 synergistic treatment has the effect of weight loss -Medicilon

GLP1-ELP and ELP-FGF21 synergistic treatment has a weight loss effect

The researchers conducted a short-term trial study to test their hypothesis that GLP-1 and FGF21 have a better effect in controlling blood sugar and suppressing weight gain, comparing the GLP-1/FGF21 combination therapy with each individual drug therapy.

The co-treatment of GLP-1 and FGF21 enhanced the inhibitory effects of monotherapy on blood sugar reduction and weight gain. Source (Science Advances)

Db/db mice were subcutaneously injected with an equimolar mixture of GLP1-ELP, ELP-FGF21, GLP1-ELP and ELP-FGF21, and blood glucose levels and body weight were measured 48 hours after injection. Compared with excipients, all treatments significantly reduced blood glucose levels, while the combined treatment resulted in blood glucose levels tending to be lower than each single drug. Treatment with ELP-FGF21 or GLP1-ELP can effectively inhibit weight gain (-0.9±0.3 and -0.2±0.6%), and the body weight increases by 2.7±0.7% within 48 hours, compared with ELP-FGF21 and GLP1 The body weight of mice treated with ELP combination was significantly reduced by 5.6±0.6%. Taken together, these data indicate that GLP-1 and FGF21 have additive effects in diabetic mice to induce weight loss and improve blood sugar control, thereby stimulating the development of drugs with dual agonistic effects of GLP-1 and FGF21, while retaining ELP components for use Sustained release.

GLP1-ELP-FGF21 dual agonist fusion protein has a sustained dose-dependent effect on body weight and blood glucose
Next, test the efficacy of dual agonist drugs in diabetic mice. The Db / db mouse model was chosen because of its extreme hyperglycemia and obesity. The high baseline weight and blood glucose level provide a broad window for identifying dual agonism. Mice were given a single subcutaneous injection of GLP1-ELP-FGF21 at the specified dose, and blood glucose levels were measured every day until all cohorts returned to baseline levels.

GLP1-ELP-FGF21 dual agonist fusion protein has an effective and sustained effect on blood sugar and body weight. Source (Science Advances)

At the two highest doses tested (750 and 1000 nmol/kg), a significant decrease in blood glucose relative to the time area under the curve was observed; however, the raw blood glucose versus time data showed that it was not the size of the effect but the duration of the effect in terms of dose The way of dependence increases. All doses can reduce blood glucose levels from >300 to<150 mg/dl, the lowest dose (250 nmol/kg) lasts for 4 days, and the highest test dose (1000 nmol/kg) lasts for 8 days. Compared with the vehicle control, all tested doses of GLP1-ELP-FGF21 have the effect of inhibiting weight gain, and the two highest doses tested both reduced body weight by 7.2±2.3%. Simultaneous analysis of pharmacokinetic data and blood glucose-time-effect data (1000 nmol/kg) found that the lowest therapeutic concentration was 100 nM, because the blood glucose level returned to baseline within the same time frame when the serum drug level fell below 100 nM . In conclusion, the treatment of obese and hyperglycemic mice with GLP-1/FGF21 dual agonist drugs has an effective and sustained effect on body weight and peripheral blood glucose levels. One injection is sufficient to maintain the therapeutic drug level and protect mice from hyperglycemia and weight gain> 7 days, which indicates that GLP1-ELP-FGF21 is suitable for a weekly dosing regimen, and it is confirmed that 1000 nmol/kg The dosage can produce the greatest therapeutic effect within the expected dosing cycle.

The GLP1-ELP-FGF21 dual agonist performed better than the long-acting GLP-1RA and GLP-1/FGF21 drug mixture in diabetic mice

In order to clarify the relative contribution of GLP-1 and FGF21 to the effective effects of dual agonists in the body and to understand the effect of incorporating the two drugs into a single molecule, the researchers combined the efficacy of GLP1-ELP-FGF21 with the GLP1-ELP single agonist Therapies, ELP-FGF21 monotherapy and preparation of equimolar mixtures of GLP1-ELP and ELP-FGF21.

Compared with long-acting GLP-1RA, GLP1-ELP-FGF21 dual agonist can provide better blood sugar control and prevent weight gain. Source (Science Advances)

The pharmacokinetic profile was evaluated for the synthesized GLP1-ELP fusion and the equimolar mixture of GLP1-ELP and ELP-FGF21. Although the absorption of each component in the mixture conforms to the zero-order release model, neither GLP1-ELP nor ELP-FGF21 can maintain a stable plasma level like GLP1-ELP-FGF21, which indicates that there are drugs in the delivery of GLP1-ELP-FGF21. Generation dynamics advantage.

After establishing appropriate controls, the researchers compared the acute and chronic metabolic effects of dual agonist treatment with the corresponding single agonist ELP fusion protein. Db/db mice were treated with GLP1-ELP-FGF21 (1000 nmol/kg), GLP1-ELP (1000 nmol/kg), ELP-FGF21 (1000 nmol/kg) and vehicle every week for 4 weeks. In the 4-week study, compared with GLP1-ELP monotherapy, dual agonist treatment further reduced weight gain (+14.1±1.6% and +25.3±1.9%, respectively). ELP-FGF21 monotherapy did not have a significant effect on body weight, indicating that the synergy between FGF21 and GLP-1 is essential for achieving weight loss.

The percentage of glycosylated hemoglobin A1c (%HbA1c) was determined before the start of the chronic dose study (day 0) and the end of treatment (day 27). %HbA1c reflects the average circulating glucose level over time and only changes with red blood cell turnover Variety. The average life span of red blood cells in mice is about 40 days, so a 4-week study is enough to cause a significant change in %HbA1c. Compared with the control, both ELP-FGF21 and GLP1-ELP monotherapy significantly inhibited the increase of %HbA1c, the dual agonist cohort showed the greatest long-term glycemic control, and the minimum change of %HbA1c was +0.3±0.2%. Therefore, compared with equimolar doses of long-acting GLP-1RA, treatment with GLP1-ELP-FGF21 dual agonist drugs can provide better blood sugar control, which may be due to the synergistic effects of GLP-1 and FGF21 components. Enhance insulin secretion and increase insulin sensitivity.

The researchers next evaluated the metabolic effects of the GLP-1/FGF21 combination therapy. Let Db/db mice receive a single subcutaneous injection of GLP1-ELP-FGF21 (1000 nmol/kg), a mixture of GLP1-ELP (1000 nmol/kg), ELP-FGF21 (1000 nmol/kg) and ELP (1000 nmol/kg) kg) as a negative control. Body weight and surrounding blood glucose levels were measured every day until the cohort returned to baseline levels, and intraperitoneal GTT (0.75 mg/kg) was performed 6 days after treatment to assess how to maintain blood glucose control for a long time.

GLP1-ELP-FGF21 dual agonist form is therapeutically superior to GLP-1 / FGF21 single agonist mixture Source (Science Advances)

After GLP1-ELP-FGF21 treatment, the environmental blood glucose level decreased from> 300 mg/dl and maintained at<150 mg/dl for about 10 days. In contrast, the 1:1 mixture group maintained blood glucose at <150 mg/dl The level was only 4 days, after which the level began to return to the baseline. The AUC analysis of environmental blood glucose versus time data confirmed that GLP1-ELP-FGF21 treatment provides superior glucose control compared to the 1:1 mixture. Although both the dual agonist and single agonist mixture treatment groups showed improved glucose tolerance, mice treated with GLP1-ELP-FGF21 recovered to near baseline levels within 60 minutes, while those treated with 1:1 mixture or ELP The animal cohort did not return to their baseline after the glucose shift. These results clearly demonstrate the strong glucose tolerance unique to dual agonist formulations.

Both combination therapies caused weight loss. The weight of the dual agonist and 1:1 mixed cohort was reduced by 5.8±0.8% and 6.5±0.7%, respectively. GLP1-ELP-FGF21 inhibited weight gain to a greater extent until day 8. Both maintained the net weight loss effect, while the treatment with the 1:1 mixture stopped the net weight loss effect only on the 6th day. These results further support the delivery of GLP-1 and FGF21 as a single molecule, and the data indicate that the regulation of drug release into the systemic circulation is more consistent.

Taken together, these findings clearly indicate that GLP-1 and FGF21 have a synergistic effect in diabetic mice. In addition, compared with the mixture of two corresponding drugs, the dual agonist formed by the fusion of GLP-1 and FGF21 with ELP can produce better therapeutic effects, thus validating the multi-agonist method of GLP-1/FGF21 combination therapy.

Results and discussion

The fusion of GLP-1 and FGF21 is driven by its complementary pharmacology, thus realizing the three criteria of an ideal combination therapy for the treatment of metabolic diseases: improving glucose metabolism, reducing food intake and increasing energy consumption. Compared with GLP-1RA therapy, GLP1-ELP-FGF21 therapy can help mice lose weight and strengthen blood sugar control in a mouse model with severe defects in energy and glucose regulation. When tested with a 1:1 mixture of long-acting GLP-1 and FGF21 single agonists, the dual agonist drugs consistently showed excellent metabolism.

The dual agonist design also has the advantage of ease of administration. The clinical application of injections is limited by volume, viscosity and pain tolerance of patients. Compared with delivering agonists on separate stents, delivering two agonists on one ELP or any polymer-based delivery stent can reduce the polymer stoichiometry by 50%, so the dual agonist approach reduces The required injection concentration and viscosity, thereby realizing a therapeutic agent with excellent stability that is easier to inject.

In summary, this study reveals the potent anti-obesity and anti-diabetic effects produced when GLP-1 and FGF21 are combined as a long-circulation and long-acting fusion, indicating that the dual agonist of GLP-1/FGF21 sustained-release preparations may be effective There is great potential in the treatment of overweight T2D patients. The drug combines a controlled release agent with an activator to form a unique conduction signal. This study not only designed a drug with dual GLP-1 / FGF21 receptor agonism, but also designed an innovative multi-agonist The medicine laid the foundation. Medicilon has a technology platform for high-end preparations such as controlled-release drug delivery, and has rich R&D experience in the research and development of controlled-release preparations. At the same time, Medicilon also has a variety of animal models of cardiovascular and cerebrovascular diseases. , Including obesity and diabetes models, Medicilon will continue to pay attention to the progress of this research, hoping to help the development of new diabetes drugs.

About Medicilon

Medicilon (stock code: 688202) was established in 2004 and is headquartered in Shanghai. It is committed to providing a full range of preclinical new drug research services for global pharmaceutical companies, research institutions and scientific researchers. Medicilon’s one-stop comprehensive service helps customers accelerate the development of new drugs with strong project management and more efficient and cost-effective R&D services. The services cover the entire process of pre-clinical new drug research in medicine, including drug discovery, pharmaceutical research and clinical trials. Pre-research. Medicilon grows together with high-quality customers at home and abroad, and provides new drug research and development services to more than 700 customers around the world. Medicilon will continue to base itself on a global perspective, focus on innovation in China, and contribute to human health!

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