Introduction: The Evolution of Incretin-Based Therapies
The landscape of metabolic medicine has been fundamentally reshaped over the last decade by the emergence of incretin-based therapies. From the early days of daily GLP-1 receptor (GLP-1R) agonists to the current era of once-weekly unimolecular dual agonists, the goal has remained consistent: achieving profound weight loss while optimizing glycemic control with minimal side effects. However, as the medical community looks beyond the successes of drugs like semaglutide and tirzepatide, a new frontier is emerging—signaling-biased agonism.
CT-388 represents a sophisticated step forward in this evolution. As a once-weekly, signaling-biased dual GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist, CT-388 aims to refine the therapeutic window by modulating how receptors respond to stimulation at a molecular level. Recent findings published in Molecular Metabolism highlight the potent translatability of this molecule from preclinical models to human subjects, suggesting that signaling bias may be the key to unlocking even greater efficacy in treating obesity and type 2 diabetes.
Mechanistic Insight: The Power of Signaling Bias
To understand the significance of CT-388, one must first understand the concept of biased agonism. Traditional agonists for G-protein coupled receptors (GPCRs), such as the native GLP-1 and GIP hormones, trigger multiple intracellular pathways. While they activate the desired cyclic adenosine monophosphate (cAMP) pathway responsible for insulin secretion and satiety, they also frequently recruit beta-arrestins, which lead to receptor internalization and desensitization. This ‘downregulation’ essentially removes the receptors from the cell surface, limiting the duration and intensity of the drug’s effect.
CT-388 is engineered to be signaling-biased. In cell-based assays, it selectively prioritizes the cAMP signaling pathway while minimizing receptor internalization compared to native ligands. By keeping the GLP-1 and GIP receptors ‘active’ on the plasma membrane for longer periods, CT-388 potentially allows for more sustained metabolic signaling. This unimolecular peptide-based approach ensures that both receptors are engaged simultaneously, leveraging the synergistic effects of GLP-1’s appetite suppression and GIP’s lipid-buffering and insulinotropic capabilities.
Preclinical Foundations: From Rodents to Non-Human Primates
Before entering clinical trials, CT-388 underwent rigorous testing in various animal models to confirm its metabolic benefits. In mice, the molecule demonstrated not only significant reductions in body weight and appetite but also substantial improvements in metabolic dysfunction-associated steatohepatitis (MASH) pathology. This is particularly relevant given the high comorbidity between obesity and fatty liver disease.
In non-human primate models (monkeys), CT-388 continued to show superior glycemic control. The consistency of these results across species provided a strong rationale for human trials, suggesting that the cAMP-biased mechanism was robust enough to translate into meaningful clinical outcomes. The pharmacokinetic profile observed in these models also supported the transition to a once-weekly subcutaneous dosing regimen in humans.
Study Design: The NCT04838405 Phase 1 Trial
The clinical evaluation of CT-388 was conducted through a Phase 1, double-blind, randomized, placebo-controlled study (NCT04838405). The primary objectives were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the compound in otherwise healthy participants with overweight or obesity.
The trial utilized two main dosing structures:
Single Ascending Dose (SAD)
Participants received subcutaneously administered single doses ranging from 0.5 mg to 7.5 mg.
Multiple Ascending Dose (MAD)
Participants received four once-weekly doses ranging from 5 mg to 12 mg.
This design allowed researchers to observe the acute effects of the drug as well as the cumulative impact over a standard one-month clinical observation period. The inclusion criteria focused on individuals who were otherwise healthy, ensuring that the primary outcomes were not confounded by complex comorbidities or prior intensive metabolic interventions.
Key Clinical Findings: Weight Loss and Glycemic Efficacy
The most striking result from the Phase 1 trial was the magnitude of weight loss achieved in a very short timeframe. By day 29—after only four weekly doses—participants receiving CT-388 showed a mean percent change in body weight ranging from -4.7% to -8.0%. In contrast, the placebo group experienced a negligible change of -0.5%.
An 8% reduction in body weight in just four weeks is clinically remarkable, often exceeding the rates observed with currently approved first- and second-generation incretins during their initial titration phases. Furthermore, the efficacy was dose-dependent, suggesting that the therapeutic ceiling for CT-388 may be quite high.
Beyond weight loss, CT-388 demonstrated potent glycemic benefits. Improvements were noted in:
Fasting Conditions
Significant reductions in fasting plasma glucose and insulin levels were observed across the treatment cohorts.
Oral Glucose Tolerance Test (OGTT)
Participants showed improved glucose handling during the OGTT, which is a critical marker for the drug’s potential in treating type 2 diabetes and prediabetes. The dual agonism appears to effectively sensitize the body to glucose loads while simultaneously reducing the systemic burden of obesity.
Safety and Tolerability Profile
Safety is a paramount concern for any new metabolic therapy, particularly in a class known for gastrointestinal side effects. CT-388 was generally well tolerated by the study participants. The safety profile was largely consistent with the known class effects of GLP-1R and GIPR agonists.
The majority of treatment-emergent adverse events (TEAEs) were categorized as mild or moderate. As expected, gastrointestinal symptoms—such as nausea, vomiting, and diarrhea—were the most commonly reported issues. These typically occurred during the dose-escalation phase and tended to diminish over time. No major safety signals or unexpected toxicities were identified, which supports the continued clinical development of the molecule into Phase 2 and Phase 3 trials.
Expert Commentary: Translational Potential and Future Directions
The success of CT-388 in this Phase 1 trial underscores the importance of ‘translational science’—the ability to take a complex molecular concept like signaling bias and successfully apply it to human physiology. Experts in the field of endocrinology note that while weight loss is the most visible outcome, the improvements in glycemic parameters and the potential for MASH resolution (as seen in preclinical models) suggest that CT-388 could be a multi-organ therapy.
However, there are limitations to consider. As a Phase 1 study, the sample size was relatively small and the duration was limited to four weeks. Long-term studies are essential to determine the durability of weight loss, the potential for plateaus, and the safety of chronic administration over years rather than weeks. Additionally, comparing CT-388 head-to-head with established dual agonists like tirzepatide will be necessary to define its exact place in the clinical hierarchy.
Biological plausibility remains strong: by reducing receptor internalization, CT-388 may require lower doses to achieve the same effect as unbiased agonists, potentially reducing the side effect burden or allowing for more aggressive weight loss in patients who are non-responsive to current therapies.
Conclusion
CT-388 represents a promising new addition to the metabolic pharmacopeia. By combining the synergistic power of GLP-1 and GIP agonism with the molecular precision of signaling bias, it has demonstrated an ability to produce clinically meaningful weight loss and glycemic improvement in a very short period. The translatability from mice and monkeys to humans has been exceptionally consistent, providing a solid foundation for further clinical evaluation.
As the medical community continues to battle the global twin epidemics of obesity and type 2 diabetes, CT-388 offers a glimpse into the next generation of precision incretin therapies—ones that are not just more potent, but more molecularly refined.
Funding and Registration
This research was supported by the developers of CT-388 (Carmot Therapeutics, now a member of the Roche Group). The clinical trial is registered at ClinicalTrials.gov under the identifier NCT04838405.
References
1. Chakravarthy MV, et al. Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP receptor agonist, on weight loss and glycemic control in preclinical models and participants with obesity. Mol Metab. 2026;103:102291.
2. Müller TD, et al. GLP-1R, GIPR, and GlucagonR ethology: From the bench to the clinic. Diabetologia. 2022.
3. Frias JP, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385:503-515.
