What clinical trials have been conducted for Dorzagliatin?

Overview of Dorzagliatin

Dorzagliatin is a first‐in‐class, dual‐acting small molecule glucokinase activator (GKA) developed primarily for the treatment of type 2 diabetes mellitus (T2DM). By targeting both pancreatic and hepatic glucokinase, dorzagliatin is designed to restore the normal function of the “glucose sensor” and improve overall glucose homeostasis. These attributes resonate with the unmet clinical needs in diabetes treatment, as dorzagliatin not only improves glycemic control but also works on modulating early-phase insulin secretion and liver glucose conversion. Its development reflects an evolving paradigm in diabetes care where restoring endogenous regulatory mechanisms is considered as important as simply reducing blood glucose levels.

Mechanism of Action

Dorzagliatin’s mechanism of action is centered on allosteric activation of glucokinase (GK), a critical enzyme in glucose metabolism that acts as a sensor in both the pancreas and liver. In the pancreas, GK activation leads to enhanced glucose-stimulated insulin secretion (GSIS), which allows for a more physiologic response to rising blood glucose levels. In the liver, the activation of GK favors the conversion of glucose into glycogen, reducing hepatic glucose output and further stabilizing glycemia. Preclinical studies have shown that dorzagliatin increases the number of GK‐immunopositive cells and upregulates GK protein expression, which has been evidenced by immunohistochemical analyses and Western blot data in animal models. Combined with the fact that dorzagliatin demonstrates a sequential zero‐order then first‐order absorption profile and linear pharmacokinetics in the therapeutic dose range, the mechanistic profile suggests that dorzagliatin provides a dual benefit: it not only addresses the secretory defects of pancreatic β‐cells but also regulates hepatic glucose output.

Therapeutic Indications

The peak clinical application of dorzagliatin is in the management of type 2 diabetes, especially for drug-naïve patients and those who have not achieved optimal glycemic control with existing therapeutic regimens. Evidence suggests that dorzagliatin may be suitable as a monotherapy, as highlighted in several Phase III trials that have demonstrated robust HbA₁c reduction and improvement in postprandial glucose levels. In addition, dorzagliatin’s mechanism provides an opportunity to address other subtypes of diabetes such as latent autoimmune diabetes in adults (LADA) and even potentially in individuals with impaired glucose tolerance (IGT). Moreover, clinical trials are also exploring dorzagliatin in combination with other antidiabetic agents (e.g., metformin, sitagliptin, empagliflozin) to harness potential synergistic effects on both glycemic control and β‐cell preservation.

Clinical Trial Phases of Dorzagliatin

Dorzagliatin’s clinical development program has spanned several phases, from early-phase pharmacokinetic and drug–drug interaction studies in healthy subjects to large-scale Phase III pivotal trials in patients with T2DM. The program is comprehensive in addressing both the monotherapy and combination therapy settings, ensuring that the efficacy, safety, and pharmacokinetic profile are evaluated in diverse populations, including special populations such as those with renal or hepatic impairment.

Phase 1 Trials

Phase 1 studies chiefly focus on safety, tolerability, pharmacokinetics, and early pharmacodynamic effects in healthy volunteers or select patient populations. For dorzagliatin, multiple Phase 1 trials have been conducted:

- Pharmacokinetic and Safety Studies: One of the early Phase 1 studies was designed to assess the pharmacokinetic profile of dorzagliatin when administered alone and in combination with agents such as esomeprazole in healthy subjects. This study established that dorzagliatin is well tolerated, exhibits a sequential absorption pattern (beginning with a zero‐order phase followed by first‐order kinetics), and has linear pharmacokinetics across a wide dose range. The trial also highlighted that urinary excretion is a minor elimination pathway, confirming that the drug’s pharmacokinetic characteristics are consistent with dose proportionality.

- Population Pharmacokinetic Analysis: A consolidated population pharmacokinetic analysis incorporated data from six clinical trials, including Phase 1 studies, to further evaluate the influence of demographic and biochemical variables such as age, body weight, and liver function on dorzagliatin clearance and distribution. Results demonstrated that body weight and factors such as AST levels significantly affect its clearance, thereby providing guidance for dose adjustment in clinical practice.

- Drug–Drug Interaction Studies: Another Phase 1 trial evaluated potential pharmacokinetic interactions between dorzagliatin and drugs such as sitagliptin. In this open-label, single-sequence study, patients with T2DM and obesity received sitagliptin alone for several days, followed by a combination of sitagliptin with dorzagliatin, and finally dorzagliatin alone. This study revealed that co-administration did not result in clinically significant pharmacokinetic interactions, lending support to future studies on combination therapy.

- DDI with Rifampicin: A dedicated drug–drug interaction trial was conducted to assess the impact of rifampicin on dorzagliatin pharmacokinetics. This study was designed as a single-dose, open-label trial in healthy subjects, and the findings indicated that dorzagliatin’s pharmacokinetic profile remains largely unaffected when administered with rifampicin. Such studies are critical to understanding potential alterations when dorzagliatin is coadministered with other medications, especially those that are CYP3A4 inducers.

- Bioequivalence and Formulation Studies: In addition to pharmacokinetic studies, a bioequivalence study compared the candidate formulation (75 mg tablets) used in pivotal Phase III trials with the formulation destined for commercial use. The results from this bioequivalence study confirmed that both formulations are comparable in terms of key pharmacokinetic parameters, ensuring that clinical trial data can be seamlessly translated into clinical practice.

These Phase 1 studies not only established an acceptable safety profile and favorable pharmacokinetic characteristics but also helped in refining the dose selection for subsequent Phase 2 and Phase 3 trials.

Phase 2 Trials

Moving into Phase 2, the focus shifts toward preliminary evaluation of efficacy in target patient populations while continuing to monitor safety and tolerability over extended periods. Although the details provided in the references are not as extensive as for other phases, several key aspects relevant to Phase 2 have emerged:

- Dose-Finding and Efficacy Explorations: Early Phase 2 studies assessed the glycemic effects of dorzagliatin, particularly its impact on fasting plasma glucose (FPG) and postprandial glucose (PPG) levels. In some Phase 2 trials, dorzagliatin was demonstrated to have a dose-dependent effect on glycemic control as measured by reductions in FPG and PPG. In these studies, improvements in β-cell function (often measured by indices such as HOMA2-β) and enhanced first-phase insulin secretion were observed, underpinning the drug’s mechanism of action.

- Selection of Optimal Doses for Phase 3 Trials: The data generated in Phase 2 studies provided the foundation for selecting the optimal dosage regimen used in pivotal Phase 3 trials. Although not elaborated in great detail in the provided materials, the observed efficacy in reducing glycated hemoglobin (HbA1c) levels and improving postprandial glycemic parameters without incurring severe adverse effects facilitated the progression to larger-scale trials.

- Investigation in Special Populations: Some Phase 2 investigations have also been aimed at evaluating dorzagliatin’s effects in specific subpopulations, such as patients with impaired glucose tolerance (IGT) or those with monogenic diabetes, to explore whether the drug can be effective beyond the classical type 2 diabetes population. These studies provided early evidence that dorzagliatin may offer benefits in terms of restoring β-cell sensitivity and improving overall insulin secretion dynamics.

Phase 3 Trials

Phase 3 trials are pivotal studies that confirm the efficacy and safety of a drug in large, well-defined patient populations. For dorzagliatin, Phase 3 trials have been extensive and have evaluated the drug as both a monotherapy and in combination with other established antidiabetic agents:

- Monotherapy Trials in Drug-Naïve Patients: A key multicenter, randomized, double-blind, placebo-controlled Phase 3 trial evaluated dorzagliatin as monotherapy in drug-naïve patients with T2DM. In this study, drug-naïve subjects were randomized to receive 75 mg dorzagliatin or placebo twice daily for 24 weeks, followed by a 28-week open-label treatment period. The primary efficacy endpoint was the change in HbA₁c levels from baseline to week 24. The results showed a statistically significant reduction in HbA₁c (with a decrease of approximately 1.07% in dorzagliatin-treated patients versus 0.50% in the placebo group) and favorable secondary outcomes such as reduction in 2-hour postprandial glucose. Notably, the trial demonstrated that dorzagliatin not only improves glycemic control but also supports restoration of β-cell function.

- Combination Therapy with Metformin: Recognizing that many patients in broader clinical practice are on background therapy, another Phase 3 trial evaluated dorzagliatin as an add-on therapy to metformin in patients with inadequate glycemic control on metformin alone. In this randomized trial, patients received dorzagliatin or placebo in addition to metformin, and the safety and efficacy endpoints (primarily changes in HbA₁c) were compared at 24 weeks. The findings confirmed that dorzagliatin has robust additive effects on glycemic control without compromising safety, making it a promising option for combination treatment in T2DM.

- Studies in Special Populations and Extended Dosing: In addition to the pivotal monotherapy and add-on trials, studies have also been conducted in patients with renal or hepatic impairment. For instance, a single-dose study in patients with renal impairment (non-dialysis end-stage renal disease) compared dorzagliatin pharmacokinetics with those in healthy volunteers, with a careful matching strategy to ensure safety. Another study evaluated the pharmacokinetics of dorzagliatin in patients with mild and moderate hepatic impairment compared to matched healthy subjects. These trials confirmed that dorzagliatin maintains a predictable and well-tolerated pharmacokinetic profile in special populations, supporting dose selection in wider clinical practice.

- Chronic Dosing and Long-Term Safety: A clinical trial investigating the chronic dosing of dorzagliatin aimed to assess its impact on insulin secretion, glucagon release, and overall incretin function over an extended treatment period (28 days or more) has been conducted. Similarly, an observational study followed patients for up to 52 weeks post-treatment to assess the progression of diabetes following dorzagliatin treatment. Although these studies are exploratory, they provide valuable insights into the durability of the glycemic control and the potential for long-term safety and efficacy.

- Post-Marketing and Real-World Studies: Recently, a post-marketing observational study was launched to evaluate the long-term safety of dorzagliatin in real-world settings in Chinese T2DM patients. Additionally, a predictive model study based on real-world data has been conducted to identify which patients have a higher likelihood of achieving glycemic targets when treated with dorzagliatin, thus supporting personalized diabetes care. There is also an interventional trial planned or in progress to evaluate the efficacy and safety of dorzagliatin in LADA patients, which may expand its indications.

Each of these Phase 3 trials has contributed to the evidence base required for regulatory approval and further commercialization planning. They have helped to define the optimal dosing regimens, establish a clear picture of the efficacy across various glycemic indices, and underline the consistent safety profile across different patient groups.

Results and Findings from Trials

The clinical trials conducted for dorzagliatin have yielded important data on both its efficacy outcomes and safety profile. The results from these studies provide a balanced view of how this novel glucokinase activator works in the real-world context of T2DM management.

Efficacy Outcomes

Across the various clinical trials and meta-analyses, dorzagliatin has consistently demonstrated robust efficacy in lowering blood glucose levels:

- Glycemic Control: In the Phase III monotherapy study involving drug-naïve patients, dorzagliatin led to a marked reduction in HbA₁c. The least-squares mean change from baseline (approximately –1.07%) was significantly greater than that observed in the placebo arm, where the change was roughly –0.50%. Additionally, significant decreases in FPG and 2-hour postprandial glucose (2h-PPG) were observed. In one meta-analysis, reductions of about 48.7 mg/dL in 2h-PPG and 9.22 mg/dL in fasting plasma glucose were reported, reinforcing the notion that dorzagliatin exerts good glycemic control through multiple pathways.

- Beta-Cell Function: One of the distinguishing features of dorzagliatin is its ability to improve β-cell glucose sensitivity and insulin secretion. Phase 1 and 2 studies analyzed first-phase insulin release and observed improvements in indices such as HOMA2-β, indicating enhanced β-cell function. This improvement is key because early-phase insulin secretion is often impaired in T2DM, and restoring it can result in better postprandial glycemic control.

- Combination Therapy Benefits: In the add-on study with metformin, dorzagliatin further enhanced glycemic control in patients whose baseline treatment was insufficient. The additional reduction in HbA₁c and the consistent improvement in postprandial glucose levels provided a rationale for its use in combination therapies. Similarly, early-phase combination studies with sitagliptin suggested no significant pharmacokinetic interactions while also showing improved glycemic parameters compared to either drug alone.

- Long-Term and Post-Marketing Outcomes: The chronic dosing studies and the observational real-world studies – including the predictive modeling study from China – highlight that the benefits of dorzagliatin may be sustained over a longer period. Patients showed improved glycemic control that was maintained over a 52-week observation period in extension studies. Such data lend confidence to the drug’s potential role in long-term diabetes management.

- Physiological Improvements Beyond Glycemia: Apart from lowering blood glucose, dorzagliatin has also shown benefits in reducing insulin resistance, as indicated by a decrease in HOMA2-IR (as reported in meta-analyses). Improvements in early-phase insulin secretion and the potential for better β-cell preservation may translate into disease-modifying effects, although definitive long-term outcome data are still needed.

Overall, the efficacy outcomes have consistently demonstrated that dorzagliatin can lower HbA₁c, improve fasting and postprandial glucose levels, and possibly enhance the endogenous insulin secretory response.

Safety and Adverse Effects

In addition to demonstrating efficacy, rigorous safety monitoring in all clinical trial phases has painted a favorable safety profile for dorzagliatin:

- Adverse Event Profile: In the pivotal Phase III trials, the overall incidence of adverse events was slightly higher in the dorzagliatin group compared to placebo. However, the majority of these events were mild and did not result in severe clinical complications. Notably, there was no significant increase in severe hypoglycemia or drug-related serious adverse events.

- Metabolic Effects: Some meta-analyses noted a modest increase in triglycerides (TG) and total cholesterol (TC) in dorzagliatin-treated patients compared with placebo. Although these increases were statistically significant (e.g., TG increased by approximately 0.43 mmol/L), they did not translate into a meaningful clinical risk in the short term. Similarly, small increases in body weight and body mass index (BMI) have been noted, but these were considered not clinically significant given the overall risk–benefit balance.

- Pharmacokinetic Safety in Special Populations: Studies in patients with renal or hepatic impairment have demonstrated that dorzagliatin’s pharmacokinetics are predictable and that the drug is well tolerated even in these groups. This is particularly important as T2DM patients often have comorbid renal or hepatic issues.

- Drug-Drug Interaction and Combination Therapy Safety: The drug–drug interaction studies, including those with sitagliptin and rifampicin, showed no clinically meaningful interactions. This suggests that dorzagliatin can be safely combined with other agents without the risk of unexpected pharmacokinetic issues.

- Long-Term Safety and Post-Marketing Observations: The post-marketing safety study that is currently underway in China is expected to provide further real-world data on the long-term tolerability of dorzagliatin. Early signals from chronic dosing studies indicate that the safety profile remains consistent over months of therapy, with minimal incidents of hypoglycemia and a manageable adverse event profile.

These safety outcomes suggest that while dorzagliatin may cause some minor metabolic shifts (mild elevations in lipids and slight weight gain), its overall safety and tolerability profile is favorable compared to the potential benefits in glycemic control.

Implications and Future Directions

The extensive clinical trial program for dorzagliatin has far-reaching implications for both T2DM treatment paradigms and future drug development in diabetes. By re-establishing more physiologic levels of insulin secretion and hepatic glucose management, dorzagliatin paves the way for a new approach that may slow or modify the progression of diabetes.

Impact on Diabetes Treatment

- Restoration of Glucose Homeostasis: Dorzagliatin’s dual mechanism not only lowers blood glucose but also addresses the underlying defects in glucose sensing. By improving both pancreatic β-cell responsiveness and hepatic glucose utilization, dorzagliatin is positioned as a drug that targets the root cause of dysglycemia rather than merely lowering glucose levels through insulin sensitization or secretion.

- Monotherapy and Combination Potential: The clinical trials have shown it to be effective both as monotherapy in drug-naïve patients and as an add-on to standard treatment (such as metformin). This flexible therapeutic profile means that dorzagliatin could serve as either a first-line agent or as part of a combination regimen, thereby broadening the available treatment options for patients with varying disease severities.

- Potential in Early Diabetes Remission: Data from the observational studies, including the diabetes remission study (DREAM) extension in which sustained glycemic control was observed after discontinuation of therapy, have raised the possibility that dorzagliatin may contribute to diabetes remission in a high proportion of patients. These findings are of substantial interest because achieving sustained remission is the ultimate goal in the management of T2DM.

- Addressing Special Populations: The planned and ongoing studies in patients with LADA and those with impaired renal or hepatic function demonstrate a commitment to evaluating dorzagliatin’s efficacy and safety in clinically challenging populations. This could lead to more personalized treatment strategies and improved outcomes in subgroups that traditionally have had fewer effective options.

- Economic and Quality-of-Life Implications: The improvement in glycemic control and β-cell function has the potential to reduce the burden of diabetes-related complications. Better management of the disease can translate into improved patient quality of life and lower healthcare costs over time. Moreover, the positive patient-reported outcomes observed in various trials suggest that dorzagliatin might have favorable implications from both clinical and quality-of-life standpoints.

Future Research and Development

- Longer-Term Efficacy and Safety Studies: Although the current Phase III trials and observational studies have provided a wealth of data over periods ranging from 24 to 52 weeks, there remains a need for longer-term studies. Future clinical trials should assess whether dorzagliatin’s benefits are maintained over several years and whether any late-emerging adverse effects, especially cardiovascular risks, occur. Extended follow-up studies and real-world registries will be crucial in this regard.

- Broader Indication Explorations: While most clinical trials to date have focused on T2DM, future studies may explore dorzagliatin’s efficacy in LADA or even in patients with impaired glucose tolerance who are at high risk of progressing to overt diabetes. Successful outcomes in these populations could expand the therapeutic indication of dorzagliatin and provide an early intervention strategy to curb disease progression.

- Combination Therapy Approaches: Given the favorable drug–drug interaction profile seen in early combination studies with sitagliptin and the promising results in add-on studies with metformin, future research might further investigate combination regimens. For example, exploring combinations with sodium–glucose co-transporter 2 (SGLT-2) inhibitors or other classes may leverage complementary mechanisms for even better control of glycemia while minimizing side effects.

- Pharmacogenomic and Predictive Modeling Studies: The development of a predictive model of achieving glycemic targets with dorzagliatin based on real-world study data points to the potential for personalized therapy. Future research could further refine these models and incorporate pharmacogenomic data to identify patients who are most likely to benefit from dorzagliatin therapy, thus optimizing efficacy and safety on an individual basis.

- Mechanistic Studies on β-Cell Preservation: While the current clinical trials have already shown improvements in β-cell function, deeper mechanistic studies might elucidate whether dorzagliatin can slow the progressive loss of β-cell mass that characterizes T2DM. Ongoing and future studies should explore biomarkers of β-cell health and assess whether early intervention with dorzagliatin leads to durable improvements in β-cell survival and function.

- Post-Marketing Surveillance and Real-World Evidence: The initiation of post-marketing safety studies in China demonstrates a commitment to monitoring the drug’s real-world performance. These data, combined with further registry and observational studies, will be essential to confirm the predicted safety outcomes and to adjust treatment guidelines as new evidence emerges.

Detailed and Explicit Conclusion

In summary, the clinical trial program for dorzagliatin has been extensive and multifaceted, covering all necessary phases from early Phase 1 studies in healthy volunteers to large-scale Phase III pivotal trials in diverse patient populations. The Phase 1 studies have established a robust pharmacokinetic and safety baseline, while Phase 2 trials have helped in dose-finding and demonstrated preliminary efficacy in reducing fasting and postprandial glucose levels as well as enhancing β-cell function. The Phase 3 trials – conducted as monotherapy, in combination with metformin, and in special populations – have consistently demonstrated significant improvements in glycemic control (with reductions in HbA₁c, FPG, and 2h-PPG), along with a manageable safety profile that includes only a slight increase in lipid parameters and no major safety concerns such as severe hypoglycemia.

From an efficacy standpoint, dorzagliatin has shown the capacity to restore more physiological glucose homeostasis by directly modulating glucokinase activity, enhancing early-phase insulin secretion, and reducing hepatic glucose production. These mechanistic benefits have translated into measurable clinical improvements that not only lower HbA₁c but also potentially improve long-term β-cell function—a critical factor in the progression of T2DM. Additionally, combination studies have underscored the feasibility of integrating dorzagliatin with existing antidiabetic treatment regimens, without compromising safety or efficacy.

Safety evaluations across all phases have been reassuring. Investigations into the tolerability of dorzagliatin in humans – including those with renal or hepatic impairment – have confirmed that, aside from modest increases in triglycerides, the adverse event profile is comparable to placebo, with no significant increase in serious adverse events or hypoglycemia. Furthermore, real-world studies and post-marketing surveillance initiatives are in progress to ensure that these safe outcomes are maintained over longer durations and in broader patient populations.

Looking to the future, the promising clinical data support the idea that dorzagliatin could revolutionize the treatment landscape for T2DM by not only offering effective glycemic control but also by potentially altering the natural history of the disease through β-cell preservation and improved glucose sensitivity. Future research directions include extending the duration of efficacy and safety studies, expanding indications to include LADA and high-risk prediabetes populations, and optimizing combination therapy regimens. In addition, further research into predictive biomarkers and pharmacogenomic determinants holds promise for personalizing therapy to maximize benefit while minimizing risks.

To conclude, the clinical trials conducted to date have provided compelling evidence of dorzagliatin’s efficacy and safety profile, underpinning its potential to serve as a cornerstone therapy for type 2 diabetes. With its dual mechanism of action, favorable pharmacokinetic properties, and positive outcomes demonstrated in large-scale Phase III trials, dorzagliatin is positioned to address significant unmet clinical needs. Continued research, including longer-term studies and investigations in special populations, will further refine its role in diabetes management and help establish its place in personalized and combination therapeutic strategies.