Photo Credit: Deepak Verma
1. In this randomized, double-blind, placebo-controlled trial, the use of once-weekly subcutaneous TG103 resulted in significant weight reduction at 12 weeks at all dosages.
2. It was deemed to be safe and effective, with pharmacokinetic findings in keeping with the weekly dose regimen recommended in preclinical studies.
Evidence Rating Level: 1 (Excellent)
Obesity, caused by complex interactions between behavioural, environmental, genetic, metabolic, and neuroendocrine factors, is the most prevalent chronic disease worldwide. It is associated with a greater burden of comorbidity, disability, and mortality, as well as economic strain on the healthcare system. While various interventions, including lifestyle modifications, behavioral therapies, and surgical procedures, are available, pharmacological treatments such as glucagon-like receptor agonists (GLP-1 RAs) are increasingly recognized for their potential in providing sustainable drug-based management of obesity. Despite the approval of several GLP-1 RAs for obesity treatment in the United States, none are approved for use in China, highlighting unmet medical needs in this population. TG103 is a recombinant protein exhibiting an affinity for the GLP-1 receptor with a long half-life, making it a possible candidate for weekly injections in the treatment of obesity. The current randomized, double-blind, placebo-controlled, multiple-dose phase 1b study investigated the safety, pharmacokinetics, and tolerability of weekly subcutaneous TG103 injection for nondiabetics in China. A total of 48 nondiabetic overweight or obese adults (mean [SD] age, 33.9 [10.0] years; mean [SD] weight, 81.65 [10.5] kg; mean BMI 29.8 kg/m2) were assigned to one of three groups (n = 16). Within each group, 12 were randomly assigned to receive TG103 and 4 were assigned to receive the placebo. Group A TG103 participants received 7.5 mg in week 1, followed by 15 mg for the remaining 11 weeks. Group B received 7.5 mg, followed by 15.0 mg, and then 22.5 mg from weeks 3-12. Group C TG103 participants received 7.5 mg, 15.0 mg, 22.5 mg, followed by 30 mg from weeks 4-12. While there were adverse events (AEs) recorded in 45 of the 48 participants (97.2% of TG103 patients and 83.3% of placebo patients), no serious AEs occurred. AEs in the TG103 group included: decreased appetite (58.3%), nausea (55.6%), diarrhea (52.8%), injection-site reaction (47.2%), hypertriglyceridemia (33.3%), vomiting (33.3%), and hyperuricemia (22.2%). Decreased appetite and gastrointestinal disturbances including vomiting, diarrhea, and abdominal distention were found to be dose-dependent. From a pharmacokinetic standpoint, the time to maximum concentration (Tmax) was 36.0, 35.8, and 48.0 hours for the 15 mg, 22.5 mg, and 30 mg target doses. In all groups, the blood concentration of TG103 stabilized by the 10th dose. The incidence of antibodies to TG103 was 22.2%. Mean weight change from baseline by day 85 was 5.65 kg (Group A; 7.24% loss), 5.35 kg (Group B; 5.79% loss), and 5.13 kg (Group C; 6.47% loss), whereas the placebo group lost only 1.37 kg from baseline. The placebo and experimental groups both saw decreases in waist circumference and waist-to-hip ratios, but did not differ significantly from one another. Systolic blood pressure (SBP) decreased the most in Group C, followed by Group B. There were no differences between Group A and placebos in SBP. To conclude, all three doses of once-weekly TG103 were well tolerated with acceptable GLP-1 RA safety profiles and pharmacokinetic parameters supporting the once-weekly dosing. Future trials are required to fully elucidate the efficacy and safety profile of TG103.
Click to read the study in BMC Medicine
Image: PD
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