Advances and Biological Evaluation of Diabetes Drugs

Introduction:

Diabetes is a chronic, metabolic disease resulting from defects in insulin secretion and varying degrees of insulin resistance. Early symptoms include increased thirst and urination, increased hunger, and blurred vision. Progressively, complications such as cardiovascular disease, peripheral neuropathy, nerve damage, myocardial disease, and kidney disease may occur. The prevalence of diabetes at younger ages is on the rise in recent years, with increases observed across all age groups. By 2045, it is projected that the diabetic population worldwide will reach 784 million (Figure1) ^[1].

Figure 1. Prediction of the prevalence of diabetes ^[1]

Diabetes Drugs and Their Mechanisms of Action (MoA)

Common diabetes medications include metformin, thiazolidinediones z(TZDs), DPP-4 inhibitors, SGLT2 inhibitors, insulin and its analogs, glucagon-like peptide-1 (GLP-1) analogs, amylin analogs, sulfonylureas, and α-glucosidase inhibitors.

Metformin and TZDs function primarily by enhancing the body’s sensitivity to insulin. GLP-1 receptor agonists work by enhancing insulin secretion and inhibit gastric emptying. SGLT2 inhibitors reduce glucose reabsorption thereby lowering blood glucose levels ^[3] (Figure 2).

Figure 2. Mechanisms of action of diabetes drugs ^[2]

In recent years, drugs developed around novel targets such as GLP-1 receptor agonists and SGLT2 inhibitors, as well as long-acting insulin, offer more effective treatment options for glycemic control and complication prevention. According to a global diabetes drugs market report, GLP-1 receptor agonists like semaglutide and dulaglutide were among the top performers. SGLT2 inhibitors like empagliflozin and dapagliflozin, and the dual GLP-1R/GIPR agonist tirzepatide, were also high achievers ^[3].

In Vitro Assay Services for Diabetes Drugs

Based on MoA of the existing diabetes drugs, WuXi Biology has established an in vitro diabetes services platform around various types of targets such as INS & analog, glucagon （GLP-1R/GIPR/GCGR）, SGLT1/2, NHRs, FFA, amylin, DPP, FGF21, kinase, and glycosidase (Table 1). This platform provides a full scale of in vitro diabetes assays to accelerate drug discovery.

Table 1. WuXi Biology in vitro diabetes services platform

Insulin and Insulin Analog Assays

The European Medicines Agency (EMA) has enacted rigorous guidelines for biosimilar medicinal products containing recombinant human insulin and insulin analogues ^[4]. To assess any differences in properties between the biosimilar and the reference medicinal product, comparative in vitro bioassays for receptor binding, as well as tests for subsequent biological activity should be performed. It is essential that the assays utilized for comparability testing have proven sensitivity to identify any pertinent differences. Furthermore, these experiments should be founded on sufficient replicates, dilutions, or time points per curve to precisely characterize the entire concentration-response or time-response relationship. Both the biosimilar and the reference product should be evaluated directly against each other in the same experiment.

Biological activity tests for insulin products should include receptor autophosphorylation and metabolic activity (glucose uptake, lipogenesis, glycogen formation, lipogenesis, as well as inhibition of stimulated lipolysis) and mitogenic activity mediated by IGF-1 receptor stimulation.

In adherence to EMA guidelines, WuXi Biology has developed extensive in vitro platforms for insulin bioactivity evaluation since 2016. Additionally, WuXi Biology operates a BF-Lab (GLP-like quality system) to ensure high quality profiling of the biological activity of insulin and insulin analogs. These platforms have streamlined preclinical IND and subsequent NDA submissions to the NMPA/FDA for a variety of clients focused on insulin analogs, including recombinant human insulin, insulin glargine, insulin detemir, insulin degludec, insulin lispro and more.

GLP-1R Assays

According to the global diabetes drugs market report, there is broad market potential for GLP-1 receptor agonist drugs (GLP-1RAs). GLP-1, a peptide hormone secreted by intestinal L cells, triggers a glucose concentration-dependent decrease in blood glucose levels. GLP-1 receptor agonists can replicate the physiological effects of GLP-1, stimulating the proliferation and differentiation of pancreatic beta cells, enhancing cell count, and boosting insulin secretion. Additionally, these agonists reduce liver glycogen synthesis, intensify the synthesis and oxidation of free fatty acids, and facilitate the binding of muscle glycogen to glucose, thereby producing hypoglycemic effects and prolonging the duration of action. They also offer benefits in weight loss and cardiovascular protection (Figure 3). Currently, approximately half of the global GLP-1R drugs in development are single targets, while the remaining half involve multi-target cooperative effects.

Figure 3. Mechanisms of Action of GLP-1^[5]

WuXi Biology has developed a series of in vitro assay platforms, supporting GLP-1RAs single-target and multi-target preclinical biological activity analysis, drug design optimization, and mechanism exploration. These platforms offer services from lead optimization and preclinical biological evaluation to IND application for GLP-1R single target, GLP-1R/GIPR, GLP-1R/GCGR dual targets, and GLP-1R/GIPR/GCGR triple targets (Figure 4).

In vitro biological activity assay results for GLP-1RAs:

Figure 4. GLP-1R related biological activity assays

Outlook

Scientists are moving beyond the conventional MoA of blood glucose reduction. Combination therapies developed around new targets such as GLP-1, SGLT2, and multi-target receptor agonists offer minimized adverse effects on the heart and kidneys. With the continued efforts of medical professionals and researchers in this field, we can expect a broader spectrum of diabetes drugs, potentially benefiting a larger population of patients.

References:

1. https://idf.org/about-diabetes/diabetes-facts-figures/
2. Tyagi, Anit, and Subbiah Pugazhenthi. “Targeting Insulin Resistance to Treat Cognitive Dysfunction.” Molecular neurobiology vol. 58,6 (2021): 2672-2691.
3. 2023H1 Diabetes Market Research Report.
4. Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues.
5. Saraiva, Francisco Kerr, and Andrei C Sposito. “Cardiovascular effects of glucagon-like peptide 1 (GLP-1) receptor agonists.” Cardiovascular diabetology vol. 13 142. 22 Oct. 2014

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