Preliminary data from the phase I study of TCMCB07, a study to assess the safety, tolerability and pharmacokinetics of the melanocortin antagonist TCMCB07 in healthy subjects.

Abstract

e15195 Background: Cachexia is a complex wasting syndrome characterized by anorexia, an involuntary loss of adipose tissue and lean body mass, and a paradoxical increase in energy catabolism. TCMCB07 is an optimized peptide antagonist of the melanocortin type 3 and 4 receptors for the treatment of cachexia. Several studies have been completed on TCMCB07 including: primary efficacy studies in rodent models of cachexia, studies to assess off-target activities, PK/ADME studies, and a 28-day GLP tox program in rats and dogs. Pre-clinical animal trials show significant results in ameliorating cancer and chronic kidney disease-associated cachexia. Based on these data, a phase 1 dose escalation study was conducted in healthy volunteers. Methods: The Phase 1 study of TCMCB07 (NCT05529849) is a single center, double-blind, randomized, sequential assessment of 5 single ascending dose cohorts (SAD) and 3 multiple ascending dose cohorts of TCMCB07. Subjects received subcutaneous administration of TCMCB07 or placebo on each of 5 consecutive days. Primary endpoints were safety and tolerability. The secondary endpoint was characterization of pharmacokinetics. Results: 40 subjects completed the SAD and 36 subjects completed the MAD portions of the trial. In a preliminary analysis of the results, there were no subjects with abnormal vital signs, no subjects with abnormal electrocardiograms, and no drug-related serious adverse events. The most common study-related adverse event was injection site reaction, graded 1 mild, or 2 moderate out of 5 (NCI CTCAE). Analysis of pharmacokinetics yielded Cmax and AUC higher than what was expected based on rat and dog studies. This resulted in lowering the cohort 3 dose so that the CMax would not exceed the cohort 5 SAD CMax. A weight difference in MAD cohort 2 and 3 between placebo and control was observed with the change in weight from end-of-study to baseline of 1.07 kg (p = 0.0195). In the same groups, on a VAS hunger scale, subjects taking TCMCB07 indicated 15% greater ease in eating meals compared to controls. This measure reached significance at one time point (p = 0.0497) but not at another (p = 0.0892). Conclusions: CB07 was well tolerated by normal healthy volunteers. Though the Phase 1 study was not designed to study efficacy, a modest difference was observed between placebo and active for body weight change and hunger. Results warrant further examination in a randomized Phase 2 study in cancer patients experiencing cachexia. Clinical trial information: NCT05529849 .