What TGR5 agonists are in clinical trials currently?

Introduction to TGR5

Definition and Function
TGR5, also known as the Takeda G protein‐coupled receptor 5, is a cell‐surface receptor that belongs to the G protein–coupled receptor family. It is activated by bile acids as well as by a suite of synthetic compounds. When TGR5 is activated, it couples to Gα proteins to trigger a rapid increase in cyclic adenosine monophosphate (cAMP) and is involved in a network of intracellular signaling cascades. These signaling events regulate numerous metabolic functions, including energy expenditure, glucose metabolism, and inflammatory responses.

Role in Human Physiology
In human physiology, TGR5 plays a pivotal role in maintaining overall metabolic homeostasis. It is expressed in diverse tissues such as the intestine, brown adipose tissue, liver, immune cells, and the gallbladder. One of its major roles is in gastrointestinal hormone regulation: activation of TGR5 in enteroendocrine L-cells stimulates the secretion of glucagon-like peptide-1 (GLP-1) which in turn influences insulin secretion and energy balance. This receptor also contributes to enhanced energy expenditure by modulating brown adipose tissue activity, and its anti-inflammatory properties make it a target for metabolic and inflammatory disorders. Overall, TGR5 is considered to be a promising target for treating conditions such as type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), obesity, and even certain inflammatory conditions.

TGR5 Agonists

Overview of TGR5 Agonists
TGR5 agonists can be broadly classified into two categories. The first group includes endogenous agonists, such as naturally occurring bile acids (e.g., lithocholic acid) which, despite their physiological role, often have limitations in potency, specificity, and safety. The second group is composed of synthetic agonists that have been developed to overcome these issues. Over recent years, several synthetic and semisynthetic TGR5 agonists have been developed with improved pharmacological profiles. Research articles and patents have described novel chemical scaffolds, including non-steroidal TGR5 agonists as well as dual agonists that target both FXR and TGR5. For example, BAR502 has emerged as a promising candidate due to its potent TGR5 activity and favorable pharmacokinetic properties, and it has been advanced into early-phase clinical trials. Other candidates like SB756050 were evaluated for metabolic indications such as T2DM; however, despite initial promise, SB756050 did not show the expected pharmacodynamic profile and its development was discontinued after Phase II assessments.

Mechanism of Action
The activation mechanism of TGR5 agonists rests on their ability to initiate intracellular signaling cascades via cAMP accumulation. Upon ligand binding, TGR5 activates Gαs proteins to stimulate adenylate cyclase, resulting in enhanced cAMP production. This in turn activates protein kinase A (PKA) and other downstream effectors that ultimately lead to clinical effects such as increased incretin secretion (notably GLP-1), enhanced energy expenditure, improved insulin sensitivity, and modulation of inflammatory cytokine production. Furthermore, some TGR5 agonists have been designed to be gut-restricted so that they act locally within the gastrointestinal tract to elevate incretin levels without causing systemic side effects such as gallbladder filling. These design strategies aim to balance potency with safety, minimizing adverse events associated with widespread receptor activation.

Clinical Trials of TGR5 Agonists

Current Trials and Phases
Among the TGR5 agonists being evaluated in clinical settings, BAR502 is currently one of the most prominent candidates. For instance, BAR502 is undergoing Phase I clinical evaluation. Its safety, tolerability, pharmacokinetics, and pharmacodynamics are being carefully studied in healthy subjects in a randomized, double-blind, placebo-controlled design. According to the detailed study design provided by trial records, BAR502 is administered in single-ascending and multiple-ascending dose cohorts to assess its overall safety. The trial registrations show that this candidate is being evaluated with registration numbers “05203367” and “06705998” on CTGOV, indicating a systematic early-phase evaluation in humans. This trial not only examines the tolerability in healthy volunteers but also helps set the stage for future therapeutic explorations in targeted patient populations, such as those with metabolic disorders.

On the other hand, SB756050 was evaluated in a separate clinical trial for subjects with type 2 diabetes mellitus. Described in the clinical trial record, this study was designed as a single-blinded, randomized, placebo-controlled, escalating-dose trial to investigate the safety, tolerability, and pharmacodynamic properties of SB756050 when administered for 6 days. Although the study provided valuable insights about the safety profile and initial pharmacodynamic responses in T2DM patients, subsequent data indicated that SB756050 produced variable effects on glucose levels—with the lower doses associated with a rise in glucose and the higher doses failing to produce the desired hypoglycemic effect. Ultimately, these findings contributed to the decision to discontinue its further development in phase II trials.

Apart from these two compounds, a number of other TGR5 agonist candidates have been described in the academic literature and patent filings. For example, dual FXR/TGR5 agonists such as INT-767 have been explored in terms of their ability to modulate bile acid signaling and incretin secretion in preclinical settings. While INT-767 has shown promising preclinical efficacy, clinical trials targeting a narrowly defined TGR5 mechanism remain in early development or are transitioning from preclinical studies to initial human testing. It is important to underscore that while many TGR5 agonists show potent activity in controlled laboratory settings, only a few have progressed into formal clinical trials that adhere to regulatory standards such as those maintained by ClinicalTrials.gov.

Another trial of note is the investigation of orally administered formulations of bile acids that may function as TGR5 activators through a gut-restricted mechanism. For example, a clinical trial described under reference evaluates a delayed-release bile acid formulation in overweight or obese patients with T2DM. Although this trial is not evaluating a chemically defined synthetic agonist per se, the pharmacological mechanism is believed to involve TGR5 activation among other bile acid receptor effects. Such therapeutic formulations exemplify an emerging strategy for harnessing the beneficial metabolic effects of TGR5 activation without incurring the systemic adverse events usually associated with non-restricted compounds.

Thus, the landscape of clinical trials for TGR5 agonists currently includes:
• BAR502, which is in Phase I trials for its safety and pharmacodynamic profile in healthy subjects.
• SB756050, which underwent a Phase I/II trial in T2DM but was eventually discontinued due to suboptimal pharmacodynamic outcomes.
• Delayed-release bile acid formulations (e.g., the study referenced) that may contribute to TGR5 activation while attempting to sidestep adverse systemic effects.

Therapeutic Areas and Indications
The primary therapeutic areas that drive the clinical evaluation of TGR5 agonists include metabolic diseases such as type 2 diabetes mellitus, non-alcoholic fatty liver disease, and obesity. The underlying rationale is that TGR5 activation significantly enhances GLP-1 secretion, which translates into improved glycemic control and enhanced insulin secretion. In addition, the modulation of energy expenditure via increased activity in brown adipose tissue offers potential for weight reduction, addressing one of the key aspects of metabolic syndrome.

Beyond purely metabolic indications, TGR5 activation is also being explored for its anti-inflammatory properties. In some preclinical studies, TGR5 agonists have been shown to reduce inflammatory cytokine production, thereby offering a rationale for their future use in inflammatory bowel diseases (IBD) and potentially other inflammatory conditions. However, the current clinical trials predominantly focus on metabolic disorders due to the strong link between TGR5-mediated incretin secretion and the regulation of blood glucose levels.

Furthermore, investigations involving gut-restricted TGR5 agonists—as exemplified by certain bile acid formulations—seek to treat metabolic disorders while mitigating the potential adverse effects, such as unwanted gallbladder filling observed with systemic TGR5 activation. This tailored approach reflects an evolving strategy where the route of administration, pharmacokinetic profile, and target tissue distribution are meticulously optimized to maximize therapeutic efficacy and minimize side effects.

Challenges and Future Prospects

Current Challenges in Development
Despite the promise that TGR5 agonists hold, several challenges have emerged. One major issue is the systemic side effects observed when TGR5 is activated in tissues such as the gallbladder. Activation in the gallbladder can lead to excessive filling and possibly increase the risk of gallstone formation. This challenge necessitates the design of agents that are either gut-restricted or have a low systemic bioavailability while still being sufficiently potent to induce local pharmacological effects.

Another challenge is the variability in pharmacodynamic outcomes. For example, the clinical development of SB756050 demonstrated that a dose-dependent effect on glucose regulation is not always predictable. At lower doses, subjects experienced an unexpected increase in blood glucose, while higher doses failed to lower glucose levels effectively. Such variable responses complicate dose-selection and further emphasize the need for predictive preclinical models before advancing candidates into extensive clinical trials.

Moreover, many TGR5 agonists, particularly those based on bile acid scaffolds, may interact with multiple receptor systems. These off-target effects can lead to safety concerns and obscure the attribution of clinical outcomes solely to TGR5 activation. The early-phase clinical trial of BAR502, while promising, is being closely monitored for potential adverse events that could emerge with systemic exposure despite its favorable profile in healthy volunteers.

In addition to safety and efficacy challenges, formulation issues remain a significant barrier. Achieving a balance between high local concentrations in the gut (to promote incretin release) and minimal systemic absorption is not trivial. Researchers are actively investigating novel drug delivery systems, such as modified-release formulations and targeted oral delivery mechanisms, to overcome this hurdle.

Future Research Directions
Looking forward, future research on TGR5 agonists should focus on several important areas. First, the development of gut-restricted compounds appears to be a promising direction. By restricting the activity of TGR5 agonists to the gastrointestinal tract, it is possible to capitalize on the capability of these compounds to promote GLP-1 secretion without exposing other tissues to the risks of systemic side effects. Several preclinical studies have already demonstrated that such an approach can improve metabolic parameters effectively in animal models.

Second, combination therapies are another strategic avenue. There is growing evidence that the beneficial effects of TGR5 agonists can be potentiated when used in conjunction with dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 inhibitors prolong the half-life of GLP-1 by preventing its rapid degradation, so co-administration with a TGR5 agonist could result in a synergistic enhancement of glycemic control. Such combination strategies are particularly attractive for treating T2DM and may also extend to the management of NAFLD and obesity.

Third, further refinement of structure–activity relationships (SAR) is crucial. Advances in computer-aided drug design, pharmacophore mapping, and molecular docking have already led to the discovery of several novel TGR5 agonists with improved potency and safety profiles. Continued research in this area, including detailed analysis of ligand bias and receptor binding kinetics, will likely yield compounds that are not only highly specific but also exhibit favorable therapeutic windows.

The translation of preclinical success into clinical benefit remains a key challenge. Future clinical studies will need to incorporate robust biomarker endpoints to ascertain the effects of TGR5 activation on incretin secretion, bile acid modulation, and inflammatory parameters. Such biomarkers will enable a more precise correlation between drug exposure, receptor activation, and clinical outcomes, thereby guiding ideal dosing regimens and optimizing trial designs.

Finally, researchers must also address the challenges of patient heterogeneity. Genetic polymorphisms or differences in receptor expression patterns across diverse populations could affect responsiveness to TGR5 agonists. Future studies may incorporate pharmacogenomic assessments to identify subpopulations that are most likely to benefit from TGR5-targeted therapies.

Conclusion
Overall, TGR5 agonists represent a class of therapeutically promising molecules with the potential to modulate energy balance, enhance incretin secretion, improve glucose metabolism, and exert anti-inflammatory effects through activation of the TGR5 receptor. The current clinical landscape, as evidenced by early-phase trials, is largely dominated by candidates such as BAR502, which is under active evaluation in Phase I studies in healthy volunteers. These early-phase trials focus on establishing the safety and pharmacodynamic profile necessary to advance the compound for metabolic indications. In contrast, although SB756050 was initially explored for its TGR5 agonistic properties in treating type 2 diabetes mellitus, variable pharmacodynamic responses led to its discontinuation in Phase II trials.

The therapeutic indications that drive these clinical efforts are primarily metabolic diseases, including type 2 diabetes mellitus, non-alcoholic fatty liver disease, and obesity, with additional potential in inflammatory conditions. The design of gut-restricted or targeted TGR5 agonists is central in overcoming adverse systemic effects, such as gallbladder filling, and in achieving the desired metabolic outcomes. Combination treatments—such as pairing TGR5 agonists with DPP-4 inhibitors—offer further avenues to enhance efficacy.

Key challenges remain in terms of dose variability, off-target effects, and the need for sophisticated delivery systems to achieve high local concentrations while reducing systemic exposure. Future research will likely focus on refining chemical scaffolds through detailed structure–activity relationship studies, exploring advanced drug-delivery technologies, and designing combination therapies that exploit the synergistic potential of TGR5 activation with other metabolic regulators. Moreover, the incorporation of pharmacogenomics and biomarker studies into clinical trial designs will help to tailor these therapies to the patient populations most likely to benefit.

In summary, while the current number of TGR5 agonists in clinical trials is limited—primarily exemplified by BAR502 in Phase I trials—ongoing research is expanding the pipeline with novel agents and combinations aimed at harnessing the full clinical potential of TGR5 activation. The development of effective and safe TGR5 agonists remains a dynamic field, with promising advances that may eventually translate into improved therapies for metabolic disorders and related diseases.