Introduction & Objective: Combinatorial therapies with incretin receptor agonists targeting multiple pathways that regulate energy balance is a promising strategy for weight loss since it potentially allows dose reduction of each drug and can help to ameliorate the associated gastrointestinal side-effects of the current monotherapies. We evaluated the combination of cagrilintide and tirzepatide on weight loss in obese rats.
Methods: Diet-induced obese Sprague Dawley male rats were dosed subcutaneously once-daily for 12 days with 3 and 10 nmol/kg of cagrilintide and tirzepatide alone or in combination at submaximal dose of 3 nmol/kg. Body weight and food intake were measured daily. Biochemical parameters in plasma were analyzed.
Results: Relative to vehicle, cagrilintide administered alone presented superior efficacy in body weight reduction (-7.22%±1.80% at 3 nmol/kg and -9.61% ± 0.52% at 10 nmol/kg) compared with tirzepatide (-2.53% ± 0.44% at 3 nmol/kg and -5.81 ± 0.86% at 10 nmol/kg). Peptide combination at submaximal dose of 3 nmol/kg each reduced body weight by -11.0 ± 0.86% (P<0.05 vs cagrilintide and P<0.001 versus tirzepatide) at the same doses, Reductions in cumulative food intake correlated with weight loss. Combination therapy was superior in decreasing ALT than cagrilintide (P<0.001) and tirzepatide (P<0.05) and plasma TGs levels were lower compared to the tirzepatide group (P< 0.001).
Conclusion: Combination therapy at submaximal doses of cagrilintide and tirzepatide achieved significantly greater weight loss and higher reduction in food intake compared to the monotherapy, suggesting the potential opportunity of this combination for further clinical development.
P. Valdecantos: Research Support; Pep2Tango Therapeutics INC. P. Rada: Research Support; Pep2Tango Therapeutics INC. S. Ghosh: Consultant; Abvance Therapeutics, Akero Therapeutics, Inc., Fractyl Health, Inc., Takeda Pharmaceutical Company Limited. C.M. Rondinone: Board Member; Pep2tango Therapeutics Inc. Stock/Shareholder; Pep2tango Therapeutics Inc. A.M. Valverde: Research Support; Pep2Tango Therapeutics INC.
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