Design of an innovative clinical development program using randomized controlled phase 2 trial data and real-world evidence from an expanded access protocol to assess mifomelatide (TCMCB07) in GI cancer cachexia.

Abstract

TPS11200 Background: Cachexia is common in GI cancers, occurring in ~50% of patients with colorectal cancer (CRC) and up to 80% of patients with pancreatic ductal adenocarcinoma (PDAC). Resulting muscle mass and energy store depletion reduces chemotherapy tolerance, often leading to dose reductions, treatment delays/discontinuation, and poorer survival outcomes (Franko J, Eur J Cancer ; 2022:174; Dunne RF, J Cachexia Sarcopenia Muscle . 2024;15:1628). Therefore, body weight preservation during chemotherapy may improve treatment effectiveness and outcomes for patients with GI cancer. The central melanocortin (MC) system, including MC3 and MC4 receptors, plays essential roles in regulating appetite, body mass, and energy homeostasis and is a logical therapeutic target to prevent and treat cachexia. Mifomelatide is a novel peptide MC3R/MC4R dual antagonist that is being studied for cancer and chemotherapy-associated weight loss. Our previously published work showed that mifomelatide was safe and effectively ameliorated cancer- and chemotherapy-associated cachexia in preclinical studies of mice, rats, and pet dogs. In a Phase 1 trial, healthy volunteers tolerated mifomelatide and did not experience vital sign or CV abnormalities or drug-related SAEs; they also experienced a modest increase in body weight and hunger compared with placebo. These findings warranted further clinical development of mifomelatide. Methods: The mifomelatide clinical development program is designed to generate a multidimensional body of evidence from clinical trial and real-world datasets that span GI cancer types and cachexia stages. First, a randomized, double-blind, placebo-controlled Phase 2 trial is evaluating mifomelatide’s effects in 120 patients with newly diagnosed mCRC and pre-cachexia or early weight loss (NCT06937177). Additionally, an intermediate-size Expanded Access Protocol (EAP) was cleared by the US Food and Drug Administration in January, 2026 to make mifomelatide available to 100 eligible cachectic PDAC patients (NCT number pending). In addition to providing mifomelatide for compassionate use to patients with PDAC who have high unmet need and no approved treatment options for their cancer cachexia, the EAP will also facilitate the collection of real-world data that, when combined with findings from the Phase 2 trial, will deepen our understanding of mifomelatide’s safety, tolerability, and potential to optimize body weight in patients with GI cancer. Collectively, our innovative hybrid approach to the mifomelatide clinical development program will generate robust insights into the benefit–risk profile of MC3R/MC4R dual antagonism with mifomelatide to treat cachexia across GI cancers and guide key design considerations for a subsequent pivotal trial. Clinical trial information: NCT06937177 .