– CT-388 administered once-weekly resulted in clinically meaningful weight loss and insulin sensitivity over a 4 week treatment period in participants with overweight or obesity without type 2 diabetes (T2D) –
– CT-868 administered once-daily over 26 weeks showed robust glycemic control with ~70% of patients with T2D achieving HbA1c in the non-diabetes range –
– Mechanistic studies in rodent models demonstrates that G-protein biased signaling in the central nervous system leads to sustained food intake suppression and weight loss –
Carmot Therapeutics Inc. (Carmot), a clinical-stage biotechnology company dedicated to developing life-changing therapeutics for people with metabolic diseases, today announced positive results from the following studies: a study of CT-388 to evaluate the safety/tolerability, efficacy, and pharmacokinetics of CT-388 in people with overweight/obesity without type 2 diabetes (T2D), a study of CT-868 assessing the efficacy and safety of CT-868 in overweight/obese patients with T2D, and a preclinical mechanism of action (MOA) study to investigate the impact of a unimolecular dual biased GLP-1/GIP receptor agonist (RA) in regulating weight loss and food intake. The results are summarized in three poster presentations taking place at ObesityWeek® October 14-17, 2023.
“Overall, we are very pleased with the results emerging from our CT-388 and CT-868 programs. Given the association of obesity and insulin resistance and risk for T2D, results from the CT-388 study showing clinically meaningful weight loss with improved glucose homeostasis and insulin sensitivity have significant implications for the potential of CT-388 as a disease-modifying therapeutic for both obesity and type 2 diabetes,” said Manu Chakravarthy, MD, PhD, Carmot’s Chief Scientific & Medical Officer. “Additionally, with CT-868, to see such a dramatic improvement in glycemic control from this Phase 2 study coupled with our prior results demonstrating the potential for GIP-mediated insulin independent glucose disposal provides robust clinical and mechanistic support for CT-868 as an effective adjunctive treatment for patients living with type 1 diabetes.”
Dr. Chakravarthy added, “Data from the CT-859, the mouse analog of CT-868, rodent experiments highlight the actions of a fully biased dual GLP-1 and GIP receptor agonist in the central nervous system to induce sustained food intake suppression and weight loss. We’re looking forward to evaluating the implications of these results for CT-868 in humans.”
Summaries of the three presentations are as follows:
CT-388, a Novel GLP-1/GIP Receptor Modulator, Improved Insulin Sensitivity in Overweight/Obese Adults
Poster-105: October 15, 11:45 am – 1:15 pm CDT
In a Phase 1 placebo-controlled, double-blind, multicenter clinical trial, 24 participants were randomized 3:1 (6 to CT-388, 2 to placebo) to evaluate the safety/tolerability, efficacy, and pharmacokinetics of ascending doses of CT-388 in participants with overweight and obesity without T2D. An oral glucose tolerance test was performed on Day -1 (baseline) and Day 23 (post the 4th dose). The results were as follows:
Statistically significant weight loss was observed after four weeks of treatment. CT-388 dosed at 5/8/12/12 mg produced 8.4% weight loss (~17 lbs) accompanied by a decrease in waist and hip circumference.
In the setting of an OGTT, glucose AUC0-120 was significantly reduced in all CT-388 cohorts compared to placebo (P0-120 and C-peptide AUC0-120 were reduced in participants with baseline BMI ≥30.In the fasted state, glucose, insulin, C-peptide, and HOMA-IR were all reduced at Day 23 compared to their corresponding baseline values in all CT-383 cohorts.
CT-388 was well tolerated in insulin-resistant obese participants with the most common adverse events (AEs) being GI-related, consistent with the incretin class.
Overall, these data support further clinical evaluation of CT-388, with higher doses while maintaining and exploring simpler titration schemes, for the treatment of obesity, T2D and other weight-related comorbidities. Carmot has designed the ongoing Phase 1/2 CT-388 clinical trial to evaluate a higher starting dose, a higher maximum dose and simpler titration schemes. Carmot expects to initiate additional Phase 2 trials for obesity and T2D.
Phase 2 Study of CT-868, a Novel Dual GLP-1/GIP Receptor Modulator, in Overweight/Obese T2D Adults
Poster-530: October 17, 11:45 am – 1:15 pm CDT
In a Phase 2, 26-week, placebo-controlled, double-blind, multicenter clinical trial, 103 participants were randomized across 3 treatment groups (placebo, CT-868 1.75mg, and CT-868 4mg) to evaluate the efficacy and safety of CT-868 administered daily by subcutaneous injection in overweight/obese T2D participants suboptimally controlled with diet and exercise with and without metformin. The results were as follows:
HbA1c improved significantly from baseline in CT-868 arms compared with placebo at Week 26 with a mean treatment difference in HbA1c for CT-868 4.0 mg vs. placebo of -2.31% (95% CI -3.03 to -1.58, p<0.001).
Approximately 70% of participants treated with CT-868 achieved HbA1c in the non-diabetes range (< 6.5%) compared to ~18% of participants who received placebo (p<0.01).
Significant improvements in cardiovascular risk factors such as lipid parameters and blood pressure were observed across the CT-868 treated groups relative to those treated with placebo.
CT-868 was well-tolerated with no treatment-related discontinuation, with the most common adverse effects being GI-related and mostly mild in severity. No clinically significant hypoglycemia was reported.
These data support continued investigation of CT-868 at higher doses in future studies.
Overall, these data demonstrate a robust effect of CT-868 on glycemic control. In addition, results from our previous preclinical experiments and phase 1b studies in participants with T2D provide mechanistic support for CT-868’s potential impact on insulin independent glucose disposal. Together, these data provide strong rationale to pursue CT-868 as an adjunct to insulin for the treatment of T1D. Carmot is currently conducting a Phase 1b mechanism of action clinical trial in patients with T1D to assess glucose homeostasis, and expects to conduct a Phase 2 proof-of-concept clinical trial in patients with overweight/obesity with T1D.
CT-859, a dual biased GLP-1R/GIPR modulator, prolongs food intake suppression & weight loss effects
Poster-529: October 17, 11:45 am – 1:15 pm CDT
In this rodent study, CT-859 (the mouse analog of CT-868) was investigated to assess the impact of a centrally administered unimolecular dual GLP-1/GIP RA in regulating food intake (FI) and weight loss (WL). CT-859, a fully cAMP-biased dual GLP-1/GIP RA that exhibits no β-arrestin coupling at either receptor, was administered to GLP-1R knockout (KO) mice and wildtype (WT) mice by intracerebroventricular injection. The results from this study are as follows:
CT-859 had no effect in the GLP-1R KO mice, but decreased food intake and body weight in WT mice in a dose-dependent manner even after 24 hours post-dose.
CT-859 produced greater reduction in body weight and food intake when compared to liraglutide at the same dose.
Biased signaling in the central nervous system is important to induce a sustained effect on food intake suppression and weight loss; these effects are centrally mediated.
All posters can be found on the Carmot website.
About CT-388
CT-388 is a once-weekly subcutaneous injectable, dual GLP-1/GIP receptor agonist being developed for the treatment of obesity and type 2 diabetes (T2D). CT-388 was designed to have potent activity on both the GLP-1 and GIP receptors but with minimal to no ß-arrestin recruitment on either receptor. This biased signaling significantly minimizes receptor internalization and consequent desensitization, which Carmot believes leads to prolonged pharmacological activity. It is currently being studied in a multi-part, multi-cohort Phase 1/2 clinical trial in people with overweight/obesity with and without T2D.
About CT-868
CT-868 is a once-daily subcutaneous injectable, dual GLP-1/GIP receptor agonist being developed as an adjunct to insulin for the treatment of people with type 1 diabetes (T1D) with overweight or obesity. CT-868 was designed to be potent on both GLP-1 and GIP receptors with no ß-arrestin recruitment to either receptor (i.e. fully biased). It is currently being studied in a Phase 1b mechanism of action clinical trial in people with T1D to assess glucose homeostasis. Carmot plans to conduct a Phase 2 proof-of-concept clinical trial in people with overweight or obesity with T1D.
About Carmot Therapeutics
Carmot Therapeutics is a clinical-stage biotechnology company dedicated to developing life-changing therapeutics for people living with metabolic diseases, including obesity and diabetes. Carmot’s expertise in metabolic biology has enabled the development of a broad pipeline of therapeutics, including three clinical candidates: CT-388 (once-weekly subcutaneous injectable, dual GLP-1/GIP receptor agonist), CT-868 (once-daily subcutaneous injectable, dual GLP-1/GIP receptor agonist) and CT-996 (once-daily oral, small molecule GLP-1 receptor agonist), and others in preclinical development. All of these are proprietary novel compounds, wholly-owned by Carmot, that have the potential to deliver an enhanced treatment response in people with metabolic diseases. For more information, visit the Carmot Therapeutics website and follow us on LinkedIn.
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