Gan & Lee Pharmaceuticals recently unveiled the positive results from Phase 1a and 1b clinical trials of its once-weekly insulin formulation, GZR4, for the first time at The 60th Annual Meeting of the European Association for the Study of Diabetes (EASD 2024). GZR4 demonstrated favorable safety and tolerability in both healthy subjects and patients with type 2 diabetes (T2DM), providing a stable glucose-lowering effect that lasts for a week with a single administration. After six weeks of treatment with once-weekly GZR4, patients with T2DM showed superior glycemic control compared to those receiving insulin degludec.

Overview of the Key Results

• In Phase 1a clinical study, GZR4 demonstrated favorable safety and tolerability profiles in healthy subjects, maintaining a stable glucose-lowering effect for up to one week with a single administration.

• In Phase 1b clinical study, patients with Type 2 diabetes mellitus (T2DM) receiving six weeks of GZR4 treatment were safe and well tolerated. GZR4 also exhibited improvements in fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and time in range (TIR) across all dosage groups, outperforming the insulin degludec (IDeg) group.

Introduction

Basal insulin is a crucial part of treatment for patients with type 1 diabetes mellitus (T1DM) and is an indispensable option for patients with type 2 diabetes mellitus (T2DM) in the later stages of disease progression¹. Currently, daily basal insulin formulations are the primary treatment, while once-weekly basal insulin can reduce the number of annual injections from 365 to 52, around an 85% reduction. This could help patients with diabetes overcome injection-related barriers, initiate insulin therapy earlier, and improve treatment adherence, ultimately enhancing their quality of life^1-3. Preclinical studies have shown that insulin GZR4 has the potential to be administered once a week. At the EASD 2024 annual meeting, the results of the Phase 1a and 1b clinical trials were presented, further investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GZR4 in Chinese healthy subjects and patients with T2DM.

Molecular Design and Pharmacological Properties of GZR4

GZR4 is an ultra-long-acting, once-weekly insulin analog developed through innovative molecular design. Three amino acid substitutions were made to the main chain of human insulin (A14E, B16H, B25H), the B30 threonine of the insulin B-chain was removed, and a 22-carbon fatty diacid was connected to the B29 position via a 12-unit oligomeric ethylene glycol (OEG) spacer. Preclinical studies have indicated that GZR4 has the potential to become a novel once-weekly basal insulin. Compared to GZR64 (an insulin analog with a similar molecular structure to insulin icodec*), GZR4 shows significantly increased affinity for human serum albumin (HSA) and a marked reduction in affinity for the insulin receptor. Unlike GZR64, GZR4 retains strong agonist activity for the insulin receptor after binding with albumin. In diabetic animal models with different disease mechanisms, GZR4’s glucose-lowering effect is approximately 2 to 3 times greater than that of GZR64 at the same dosage⁴.

China Phase Ia Trial

Trial Title：A single-center, single-dose, randomized, placebo-controlled, dose-escalation study to evaluate the safety, tolerability, PK, and PD of GZR4 in healthy adult male subjects

Registration Number：CTR20222273

Key Inclusion Criteria:

• Healthy males aged 18–45 years (both included)

• BMI 19-24 kg/m2

• Normal insulin secretion and glucose tolerance

• HbA1c ≤6%

Dose Setting

• Insulin Degludec (IDeg): 0.4 U/kg (2.4 nmol/kg)

• GZR4 Injection: four dosage groups: 1, 3, 6, 12 nmol/kg

Endpoints

• Primary endpoint: the incidence of adverse events

• Key secondary endpoints：

• PK characteristics after single administration of GZR4；

• PD characteristics after single administration of GZR4 and Insulin Degludec

Trial Results

• In healthy subjects, GZR4 demonstrated favorable safety and tolerability with no serious adverse events (SAEs) reported, and no discontinuations due to the adverse events related to investigational products.

• The glucose-lowering effect of GZR4 persists for approximately one week: the glucose infusion rate on day 7 (AUC_GIR144-168h) was approximately 80% of that on day 2 (AUC_GIR24-48h) in subjects receiving 12 nmol/kg GZR4. Meanwhile, model-predicted daily proportion of the glucose-lowering effect of GZR4 is distributed evenly over the week.

• The AUC_GIR,24-48h and AUC_GIR,144-168h of 6 nmol/kg GZR4 were comparable to the 24-hour GIR (AUC_GIR,0-24h) for the 0.4 U/kg (2.4 nmol/kg) of IDeg (37.84 ± 9.86 versus 40.60 ± 14.39 h*mg/kg/min, respectively), suggesting that the average daily glucose-lowering effect of GZR4 is comparable to that of IDeg. Convert accordingly, it is estimated that the potency of GZR4 is approximately 2.5-fold greater than that of IDeg when evaluating based on a similar molar concentration.

China Phase Ib Trial

Trial Title: A study evaluating the safety, tolerability, PK, and PD of multiple doses of GZR4 in Chinese patients with T2DM

Registration Number: CTR20230491

Key Inclusion Criteria

• Males or females aged 18–65 years (both included)

• BMI 18.5-35 kg/m2

• Diagnosed with T2DM for over 3 months

• 6.5% ≤HbA1c ≤10.0%

• FBG ≤13.9 mmol/L

• On basal insulin treatment for over 2 months

Dose Setting

• Insulin Degludec (IDeg): replaced with the equal amount of daily basal insulin according to the dosage before enrollment

• GZR4 Injection: three dosage groups: 6, 8, 12 nmol/kg

Endpoints

• Primary endpoint: the incidence of adverse events

• Key secondary endpoints：

• PK characteristics after multiple administrations of GZR4；

• PD characteristics after multiple administrations of GZR4 and Insulin Degludec

Trial Results

• The maximum plasma concentration (C_max) of GZR4 increased dose-dependently, while the time to maximum concentration (T_max) and half-life （T_1/2） were approximately 32 hours and 135 hours at steady state, respectively.

• After 6 weeks of treatment, the FBG decreased dose-dependently (-1.77 ± 0.20, -2.03 ± 0.66, and -2.75 ± 0.71 mmol/L for GZR4 in 6, 8, and 12 nmol/kg groups, respectively), which outperformed the IDeg group (a reduction of 1.12 ± 0.36 mmol/L compared to baseline).

• After 6 weeks of treatment, the 6 nmol/kg GZR4 group demonstrated a reduction in HbA1c of 0.76 ± 0.14%, compared to the reduction of 0.13 ± 0.21% in the IDeg group.

• In patients with T2DM, GZR4 demonstrated good safety and tolerability. No serious adverse events were reported in all treatment groups; the most frequently reported treatment-emergent adverse event was hypoglycemia, but no severe hypoglycemia occurred.

Discussion and Future Prospects

Enhancing Insulin Efficacy and Reducing Injection Burden

In clinical studies, GZR4 required a lower dose to achieve a comparable glucose-lowering effect, indicating its higher potency. This is attributed to GZR4’s unique molecular design, which enhances its drug potency. Generally, higher drug potency allows for ideal biological effects at relatively lower doses5. In the Phase 1a clinical study, GZR4’s potency was estimated to be approximately 2.5 times that of insulin degludec. This was demonstrated by GZR4’s significantly lower molar concentration dose compared to insulin degludec for a similar glucose-lowering effect. GZR4 required only 6 nmol/kg per week, while insulin degludec required 2.4 nmol/kg (0.4 U/kg) daily, totaling 16.8 nmol/kg per week. Moreover, in preclinical studies, GZR4 also demonstrated superior efficacy compared to insulin icodec (a self-synthesized insulin icodec analog). In Type 1 diabetic rats and Type 2 diabetic mice models, the molar concentration dose of GZR4 required to achieve a similar glucose-lowering effect was much lower than that of insulin icodec4. This advantage is likely related to GZR4’s stronger agonist activity for the insulin receptor after binding with serum albumin (HSA). Therefore, it is anticipated that GZR4 will require a significantly lower weekly dosage compared to insulin icodec for achieving glycemic targets, demonstrating its dosage advantage in clinical applications.

Reducing Dosage May Alleviate Injection-related Anxiety

In contrast to GLP-1 analogs, which may achieve enhanced efficacy by increasing the administered dose, insulin therapy is primarily focused on achieving target blood glucose levels in patients with diabetes while minimizing adverse events such as hypoglycaemia. Consequently, if patients can reduce their insulin dosage while effectively controlling their blood glucose, they can expect to have an improved overall experience of insulin therapy.

Because once-weekly insulin formulations require a single injection of the entire week’s basal insulin dose, doctors and patients may experience psychological pressure due to the large dosage, this could lead to resistance in initiating once-weekly insulin therapy6. Since GZR4 is expected to reduce the weekly insulin dosage required for achieving glycemic targets, GZR4 may help alleviate such concerns, making it easier for healthcare providers to accept this new medication, while also providing patients with a better and more convenient treatment experience.

Currently, there is only one once-weekly insulin formulation available globally. GZR4 is expected to become the first domestically produced once-weekly insulin formulation in China. Patients will only need to inject once per week to effectively control blood glucose, ushering in a new era for domestically produced once-weekly insulin therapy.

About Profil Institute

Founded in 1999, Profil is a unique full-service CRO with an excellent record for professional conduct and scientific expertise in clinical research on diabetes and other metabolic diseases. The Profil Institut für Stoffwechselforschung GmbH (in English Profil Institute for Metabolic Research), began life as a spin-off of the Department of Metabolic Diseases and Nutrition at the University of Düsseldorf. Its co-founder, Tim Heize, wished to create a dedicated CRO that would address the challenges of diabetes and obesity research and treatment. The company’s achievements are a testament to that vision. Over the years, Profil has implemented numerous sophisticated methods for pharmacodynamic characterization of the effects of compounds in early phase trials, and Profil has been involved in the development of all the currently available major novel insulins, including insulin glargine, insulin degludec, and insulin icodec, etc⁷.

Dr. de Vries obtained board licenses in Internal Medicine and Endocrinology at the VU University Medical Centre, Amsterdam. He was a professor of Internal Medicine at the University of Amsterdam's Faculty of Medicine from 2016 to 2023. Having joined Profil as of 2017, he maintains his academic position for one day per week. Dr. de Vries has been Principal Investigator in numerous clinical trials and has published more than 250 peer-reviewed scientific publications. He is a frequently invited speaker at international diabetes meetings, and has been a editorial board member of Diabetes Care, the Journal of Diabetes Science and Technology, and International Associate Editor of Diabetes Technology & Therapeutics⁷.

References

[1] Rosenstock J et al. Basal weekly insulins: the way of the future. Metabolism. 2022, 126:154924.

[2] Rosenstock J et al. Once-Weekly Insulin for Type 2 Diabetes without Previous Insulin Treatment. N Engl J Med. 2020, 383(22):2107-2116.

[3] Trevisan, R., Conti, M. & Ciardullo, S. Once-weekly insulins: a promising approach to reduce the treatment burden in people with diabetes. Diabetologia, doi:10.1007/s00125-024-06158-9 (2024).

[4] WANCAI XING, WEI CHEN, YINING ZHANG, JING GAO, ANSHUN HE, JUN ZHANG, YING DENG, FANGKAI XUE, YONGCHUN WANG, HAO FU, RUNYAO ZHANG, JINHUI HUANG, ZHONGRU GAN; 823-P: Molecular and Pharmacological Properties of GZR4, a Once-Weekly Insulin Analog. Diabetes 14 June 2024; 73 (Supplement_1): 823–P. https://doi.org/10.2337/db24-823-P.

[5] Abimbola Farinde , Drug Action. MSD manuals. https://www.msdmanuals.cn/home/drugs/drug-dynamics/drug-action 

[6] Rosenstock, Julio et al. “The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa.” Endocrine reviews vol. 45,3 (2024): 379-413. doi:10.1210/endrev/bnad037

[7] About Profil. Profil Institute. https://www.profil.com/organization/about-profil

About Gan & Lee

Gan & Lee Pharmaceuticals developed the first Chinese domestic insulin analog. Currently, Gan & Lee has six core insulin products, including five insulin analog varieties: long-acting glargine injection (Basalin^®), fast-acting lispro injection (Prandilin^™), fast-acting aspart injection (Rapilin^®), mixed protamine zinc lispro injection (25R) (Prandilin^™25), aspart 30 injection (Rapilin^®30), and one human insulin injection - mixed protamine human insulin injection (30R) (Similin^®30). The company has two approved medical devices in China, namely reusable insulin injection pen (GanleePen), and disposable pen needle (GanleeFine^®).

In China's 2024 National Insulin-Specific Centralized Procurement, Gan & Lee Pharmaceuticals ranked  first among all selected companies in terms of procurement demand for insulin analogs. The company is also making strides in international markets, with the disposable pen needle (GanleeFine^®) approved by the US Food and Drug Administration (FDA) in 2020 and received GMP inspection approval from the European Medicines Agency (EMA) in 2024. These achievements significantly boost Gan & Lee’s competitiveness in both international and domestic markets.

In the future, Gan & Lee will strive for comprehensive coverage in diabetes treatment. Moving forward with its mission to become a world-class pharmaceutical company, Gan & Lee will also actively develop new chemical entities and biological drugs, focusing on treatments for metabolic diseases, cardiovascular diseases, and other therapeutic areas.