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Diabetes mellitus, commonly known as diabetes, is a chronic, metabolic diseases characterized by hyperglycemia, which over time, can lead to long-term damage, dysfunction, and failure of various organs especially the eyes, kidneys, nerves, heart, and blood vessels. As one of the most common chronic diseases, diabetes accounts for a large proportion of healthcare costs. Due to the poor efficacy of oral hypoglycemic drugs in the later stages of the diabetes and the lack of patient compliance with mutiple injections, there is a huge demand for new therapeutic drugs and methods in clinical practice.

Focused on the diabetes field for over two decades, Gan & Lee has developed a wide range of anti-diabetic drugs, including long-acting insulin, rapid-acting insulin and premixed insulin. In addition, Gan & Lee is actively developing glucagon-like peptide-1 (GLP-1) receptor agonists, fourth-generation ultra-long-acting once-weekly insulin and dual insulin analogues, aiming to build an anti-diabetic product matrix covering both insulin and innovative hypoglycemic drugs.

Besides diabetes, Gan & Lee is also developing new chemical entities for the treatment of cancer, autoimmune disease, blood disease, skin disease, etc. To learn more about the company's research and development strategy and updates in these therapeutic areas, please visit Gan & Lee's website at www.ganlee.com.

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Q & A

GZR18

What is GZR18？

GZR18 is an investigational glucagon-like peptide-1 receptor agonist that Gan & Lee is developing for the treatment of type 2 diabetes mellitus (T2DM) in adults.
What is the difference between glucagon and glucagon-like peptide- 1 (GLP-1)?

Glucagon is a hormone, formed in the alpha cells of the pancreas, that is released when blood glucose levels are low. It promotes the breakdown of glycogen from the liver into glucose when glucose levels are very low[1]. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, produced in intestinal L cells, that stimulate insulin secretion after an oral glucose load or meal. In addition, this hormone can also inhibit the production of glucagon from pancreatic alpha cells if blood sugar levels are high. In type 2 diabetes, this process of insulin secretion via GLP-1 can be altered or even absent[2].
What is the difference between GLP-1 receptor agonists and insulin?

GLP-1 receptor agonists are utilized to help promote the secretion of insulin in type 2 diabetes patients. In addition, GLP-1 receptor agonists are dependent upon high levels of plasma glucose. Therefore, GLP-1 receptor agonists have less risk of hypoglycemia than insulins, indicating a more favorable safety profile[3]. GLP-1 receptor agonists may also be administrated less frequently than insulin, which can potentially lead to improved patient adherence.
How are GLP-1 receptor agonists utilized in type 2 diabetes treatment?

Type 2 diabetes treatment is dependent upon many factors such as the risk for atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and heart failure (HF). For example, GLP-1 receptor agonists with proven cardiovascular disease (CVD) benefit may be recommended in patients who have ASCVD, demonstrate high ASCVD risk, or CKD. Whereas GLP-1 receptor agonists are not suggested for patients experiencing heart failure[4].

In addition, GLP-1 receptor agonists may also be considered in patients without any indicators of high-risk or established ASCVD, CKD, or HF. GLP-1 receptor agonists may be considered in combination therapy as well in patients who need to minimize weight gain or promote weight loss[4].
Are there GLP-1 receptor agonists approved for diabetes treatment globally?

Currently, multiple GLP-1 receptor agonists are approved worldwide for the management of patients with type 2 diabetes. Examples include semaglutide, dulaglutide, liraglutide, exenatide, and lixisenatide, which are approved in China.
What was the rationale for studying GZR18 as a potential treatment of diabetes?

GZR18 is a GLP-1 receptor agonist. The GLP-1 is an incretin hormone; activation of GLP-1 receptors stimulates insulin secretion and inhibits glucagon, thereby lowering glucose levels. Patients with T2DM often produce a decreased levels of GLP-1, which can lead to decreased insulin secretion, increased insulin resistance, and ultimately hyperglycemia. In preclinical studies, GZR18 showed glucose-lowering effects in T2DM animal models.
What is the difference between GZR18 from other GLP-1 receptor agonists?

GZR18 was developed as a long-acting formulation, which may allow it to be injected subcutaneously less frequently. Compared to daily formulations of GLP-1 analogs, GZR18 can be injected less frequently, reducing patient pain, and improving patient compliance. Nevertheless, early clinical data suggest that GZR18 is feasible for biweekly dosing, and this conjecture will be tested in subsequent exploratory clinical trials. Nevertheless, early clinical data suggest that GZR18 is feasible for biweekly dosing, this conjecture will be tested in subsequent exploratory clinical trials.
Can GZR18 be used in another therapeutic area besides diabetes?

Preclinical data suggests that GZR18 has potential to reduce weight.Some finished clinical studies suggest that GZR18 has weight-loss effects in humans. Follow-up clinical studies will continue to validate the use of GZR18 in overweight/weight control indications.
Have there been any studies completed with GZR18 in humans?

GZR18 has completed a first In-human (FIH), double-blind, randomized, placebo-controlled, dose-escalation Phase Ia study in China (GL-GLP-CH1002). Two independent multicenter, randomized,double-blind, placebo-controlled Phase Ib/IIa clinical studies are currently underway to evaluate the safety, tolerability, pharmacokinetics, and efficacy of GZR18 in adult Chinese patients with T2DM and obesity/overweight (GL-GLP-CH2001 and GL-GLP-CH2002). A randomized, double-blind, placebo-controlled, dose-escalation Phase Ic clinical study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose GZR18 injection in obese/overweight subjects is also planned (GL-GLP-CH1017).

GZR101

What is GZR101？

GZR101 is a premixed dual insulin compound preparation made by co-formulating the investigational long-acting basal insulin GZR33 and fast-acting insulin aspart. It is expected that GZR101 can simulate the biphasic pattern of physiological insulin secretion under once-daily administration, take into account both fasting and postprandial blood glucose control, stabilize blood sugar steadily, and improve the rate of glycemic control rate. GZR101 is also expected to simplify treatment, improve patient compliance, and reduce treatment burden to optimize long-term diabetes management and help reduce or delay the onset of complications.
What was the rationale for studying GZR101 as a potential treatment for diabetes?

People with T2DM often produce lower insulin levels or develop insulin resistance, which can lead to hyperglycemia. GZR101, a dual-insulin compound preparation made by mixing ultra-long-acting basal insulin GZR33 and fast-acting insulin aspart, can simulate the biphasic pattern of physiological insulin secretion and maintain the body's absorption and utilization of glucose during both the fasting and postprandial state, thereby lowering blood glucose levels. In preclinical studies, GZR101 has shown a dose-dependent hypoglycemic effect in T2DM animal models.
What are the potential clinical advantages of GZR101?

GZR101, as a dual-insulin compound preparation composed of a new structural molecule and a marketed drug, has a clear mechanism of action. The single administration of the two premixed insulins has the potential to better simulate the biphasic secretion pattern of physiological insulin, taking into account both fasting and postprandial glycemic control.

Compared with the traditional treatment method of daily injection of 1 injection of long-acting basal insulin and 3 injections of fast-acting mealtime insulin, the usage of GZR101 injection is expected to be a subcutaneous injection once a day, which reduces the pain of multiple injections and is expected to improve patient compliance.

Preclinical data suggest that GZR101 is expected to be administered at a lower dose, smaller administration volume, and less irritating than the marketed similar product, thereby expecting a good clinical development prospect.
What nonclinical studies were conducted with GZR101?

GZR33, a constituent of GZR101, has been evaluated in vitro for affinity to human albumin and for efficacy in T2DM animal models, while its pharmacokinetic and safety profile have been evaluated in rats and beagle dogs.

Another constituent of GZR101, insulin aspart, is a marketed drug. Its pharmacodynamics, pharmacokinetics, general pharmacology, immunogenicity and immunotoxicity, allergy studies, local irritation studies, and long-term toxicity studies data have been provided at the time of Investigational New Drug (IND) application.

GZR101 injection has evaluated the efficacy in type 1 and type 2 diabetes animal models. In addition, the absolute bioavailability and pharmacokinetic characteristics of single-dose GZR101 injection and the toxicokinetic study of repeated-dose have also been evaluated in rats.
Have there been any studies completed with GZR101 in humans?

GZR101 has completed a first-in-human (FIH), single-site, single-dose, randomized, double-blind, placebo-controlled, dose-escalation phase I study in China.
What are the objectives of the GZR101 FIH trial in China?

The primary objective of the GZR101 FIH trial in China is to investigate the safety and tolerability (including local tolerability) of GZR33 and GZR101 in healthy adult male subjects.

The secondary objectives are to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of GZR33 and GZR101 in healthy adult male subjects.

GZR4

What is GZR4？

GZR4 is the fourth-generation ultra-long-acting once-weekly insulin independently developed by Gan & Lee Pharmaceuticals. Its primary function is to activate insulin receptors to regulate glucose metabolism. It can increase glycogen, fatty acid, glycerol and protein synthesis, and amino acid uptake in insulin target tissues. Also, it reduces glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism, and amino acid export. GZR4 is expected to be administered once a week by subcutaneous injection to achieve stable control of basal blood glucose for one week. In addition, it can potentially reduce the pain of injection, improve patients' compliance with insulin therapy, and optimize long-term treatment management, with high clinical benefits.
What was the rationale for studying GZR4 as a potential treatment for diabetes?

GZR4 is an investigational ultra-long-acting insulin analog once-weekly preparation, which has been modified in the molecular structure of human insulin. Its hypoglycemic mechanism is the same as that of human insulin. The primary function of human insulin is to activate insulin receptors to regulate glucose metabolism. In insulin target tissues, it can increase glycogen, fatty acid, glycerol, protein synthesis, and amino acid uptake while reducing glycogenolysis, gluconeogenesis, ketosis, lipolysis, protein catabolism, and amino acid export. The long-acting mechanism of GZR4 is as follows:
1) The amino acid site is mutated on the basis of the structure of human insulin, and the amino acid at the end of the B chain is removed, which significantly improves the anti-enzymatic hydrolysis ability of the drug molecule. In addition, this modification significantly reduces the insulin's affinity to the insulin receptor, which delays the process of receptor-mediated drug degradation and clearance in the body;
2) The addition of fatty acid side chains enhances the reversible binding to human serum albumin (HSA) so that GZR4 can be dynamically and slowly dissociated from HSA to delay the metabolism and clearance by the kidneys, thereby further prolonging its half-life in vivo.
What are the potential clinical advantages of GZR4?

Compared with the marketed long-acting insulin such as glargine, GZR4 has the following advantages:
1) Longer half-life, more stable blood drug concentration, more stable expected drug effect, and less blood glucose interday variability and hypoglycemia risk;
2) Lower dosing frequency, extend from once a day (7 times a week) to once a week, and the drug effect can last for a week, which greatly facilitates the use of patients;
3) Helps overcome the obstacles of injection with the potential to improve patient compliance, making patients willing to start insulin therapy earlier, thereby optimizing long-term diabetes management and improving treatment compliance rates.
What nonclinical studies were conducted with GZR4?

GZR4 has evaluated the efficacy in type 1 and type 2 diabetes animal models. In addition, the pharmacokinetic characteristics of single-dose GZR4 injection and the toxicokinetic study of repeated-dose have also been evaluated in rats and Beagle dogs.
Have there been any studies completed with GZR4 in humans?

GZR4 has completed a first-in-human (FIH), single-site, single-dose, randomized, single-blind, placebo-controlled, dose-escalation phase 1 study in China.
What are the objectives of the GZR4 FIH trial in China?

The primary objective of the GZR4 FIH trial in China is to investigate the safety and tolerability (including local tolerability) of GZR4 in healthy adult male subjects.

The secondary objectives are to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of GZR4 in healthy adult male subjects.

Insulin Glargine U300

What is the insulin glargine U300?

Toujeo^® (insulin glargine U300) is an improved version of Lantus^® (insulin glargine U100) developed by Sanofi. It received marketing approval from the US FDA and EU EMA in 2015, for use in adult patients with diabetes. Then, the FDA and EMA approved an expanded indication for use in children and adolescents aged six years and older with diabetes in 2019 and 2020, respectively. In 2018, Sanofi developed insulin glargine U300, which completed a Phase III clinical trial in China and received marketing approval from the NMPA in 2020. The study showed that at the same injectable dose, the injectable volume of insulin glargine U300 was reduced by two-thirds, so the surface area of the subcutaneous reservoir of insulin glargine was smaller, from which insulin glargine was released more smoothly and durably, with slower subcutaneous absorption, resulted in a more prolonged absorption time and flatter blood concentration-time curve. The hypoglycemic effect of insulin glargine U300 was similar to that of insulin glargine U100. However, during the dose adjustment phase, the glycemic decrease of patients treated with insulin glargine U300 was more stable[5][6]. In addition, the incidence of proven hypoglycemia (throughout the day and night) was lower in patients treated with insulin glargine U300 than in patients treated with insulin glargine U100. Therefore, insulin glargine U300 is recommended by domestic and international guidelines as the preferred choice of insulin therapy[3].
What was the rationale for studying insulin glargine U300 as a potential treatment for diabetes?

Insulin glargine U300 is a long-acting insulin analog produced by genetic recombination technology, and its glucose-lowering effect is similar to that of the insulin pump. Like insulin glargine U100, it can increase glucose utilization, accelerate anaerobic enzymolysis and aerobic oxidation of glucose, promote the synthesis and storage of liver glycogen and muscle glycogen, and promote the conversion of glucose into fat and inhibit glycogenolysis and gluconeogenesis, thus lowering blood glucose. In addition, it can promote the synthesis of fat and inhibit lipolysis so that the production of ketone bodies can be reduced and the various symptoms of ketoacidemia can be corrected. Furthermore, it can promote the synthesis of protein and inhibit the decomposition of protein.

Compared with natural human insulin, the last aspartic acid at the carboxyl end of the A chain is replaced by glycine, making the hexamer more stable; two arginines are attached to the 31 and 32 positions at the carboxyl end of the B chain, leading to an increase in the isoelectric point from 5 to 6. After these molecular changes, insulin appears as a colorless and transparent solution under acidic conditions, while its solubility is very low under physiological conditions. Its polymerization and solubility decrease immediately after subcutaneous injection, forming insulin glargine precipitates, thus being delayed in absorption and prolonging the duration of action.
Are there insulin glargine U300 products approved for diabetes treatment globally?

Currently, there is only one insulin glargine U300 formulation approved for the indication of adult type 2 diabetes globally, that is, the Insulin glargine U300 Toujeo^®, which is also approved for marketing in China.
What are the potential clinical benefit of insulin glargine U300 compared to insulin glargine U100?

Insulin glargine U300 applies a unique subcutaneous reservoir micro-precipitation technology, means that after subcutaneous injection, insulin glargine forms a deposit with no fixed direction and forms a subcutaneous reservoir to achieve a smooth and slow release in the physiological PH[5][6][7][8][9]. Compared to insulin glargine U100, the PK/PD profile of insulin glargine U300 is smoother and more consistent with the physiological basal insulin secretion pattern[10]. Studies have shown that when insulin glargine U300 is compared to insulin glargine U100 and insulin degludec, the PK/PD of glargine insulin U300 is more durable and stable. It has also been shown that when insulin glargine U300 is injected subcutaneously, 80% of it is metabolized within 24 h to exert hypoglycemic effects, and the remaining 20% is metabolized the next day. Therefore, the daily dose of insulin glargine U300 is balanced with the metabolic dose, and there is no risk of accumulation[5][11][12][13].
What nonclinical studies were conducted with Gan & Lee insulin glargine U300?

The results of preclinical pharmacokinetic studies of insulin glargine U300 produced by Gan & Lee Pharmaceuticals showed prolonged absorption time to peak, reduced peak concentration, reduced systemic exposure, and longer mean residence time compared to insulin glargine U100.

Meanwhile, allergic reactions to repeated dosing and toxicokinetic studies were evaluated in rats, guinea pigs, and beagle dogs with Gan & Lee insulin glargine U300.
Have there been any studies completed with Gan & Lee insulin glargine U300 in humans?

Gan & Lee insulin glargine U300 has completed a single-center, randomized, double-blind, single-dose, two-agent, two-sequence, four-period repeated crossover design controlled evaluation of the bioequivalence and safety of Gan & Lee Insulin glargine Injection (3ml: 900 units/stem) and Toujeo^® in healthy subjects.
What are the objectives of the Gan & Lee glargine U300 FIH trial in China?

The primary objective was to compare the pharmacokinetics and pharmacodynamics of bioequivalence of insulin glargine U300 (test product) manufactured by Gan & Lee Pharmaceutical Co., Ltd. with that of insulin glargine injection (Toujeo^®, reference product) of German origin by Sanofi Aventis, using the euglycemic clamp technique in healthy Chinese male subjects.

The secondary objective was to evaluate the safety of insulin glargine U300 in healthy Chinese male subjects.
What is the study design for the Gan & Lee insulin glargine U300 FIH trial in China?

The trial applies a single-center, randomized, double-blind, single-dose, two-agent, two-sequence, four-period with Toujeo^® repeated crossover control design. See the flowchart below:
What is the key study result for the glargine U300 FIH trial in China?

The PK and PD of insulin glargine injection (3ml: 900 units/stem) produced by Gan & Lee Pharmaceutical Co., Ltd. are bioequivalent to those of insulin glargine injection (Toujeo^®) produced by Sanofi Aventis, and the two agents have similar safety profiles.