AWT038: Dual GDF15-IL-6 neutralization for cancer cachexia

Cancer cachexia is a multifactorial syndrome marked by involuntary weight loss, anorexia, muscle wasting, and profound fatigue, leading to diminished quality of life and poorer response to therapy. It affects ~50-80% of patients with advanced cancer and contributes to up to ~30% of cancer deaths. Cancer cachexia is driven by overlapping anorexigenic and inflammatory signals. GDF15 engages GFRAL in the hindbrain to suppress appetite and drive weight loss, and clinical GDF15 blockade (e.g., ponsegromab) has increased body weight, appetite, activity, and lean mass in randomized trials. By contrast, IL-6 is a key mediator of inflammation-associated muscle wasting. Phase I/II studies of anti-IL-6 agents (e.g., clazakizumab/ALD518) attenuated lean-mass loss and fatigue. We engineered AWT038, a novel bispecific fusion protein comprising an engineered high affinity human GFRAL domain fused to an anti-IL-6 antibody. The GFRAL moiety bound GDF15 with KD = 0.11 nM and achieved GDF15 neutralization comparable to ponsegromab in vitro; the anti-IL-6 arm bound IL-6 with KD = 0.13 nM and preventing IL-6 from engaging IL-6R. n a GDF15-secreting HT1080 xenograft cachexia model in SCID mice, AWT038-treated animals showed reduced circulating free GDF15 levels and body-weight gains comparable to ponsegromab. In cynomolgus monkeys, AWT038 was well tolerated at 10 and 30 mg/kg with a terminal half-life of approximately 100 hours and no detectable anti-drug antibodies. AWT038 also exhibits high thermostability (Tm > 65 °C) and favorable developability, being readily manufacturable. By simultaneously neutralizing GDF15-GFRAL anorexigenic signaling and IL-6 driven inflammatory catabolism, AWT038 addresses two non-redundant drivers of cancer cachexia within a single molecule. This dual blockade supports development as supportive care for patients with advanced cancers and elevated GDF15 and/or IL-6, including those receiving platinum-based chemotherapy where GDF15 rises and weight loss is common. If confirmed in clinical studies, AWT038 could complement or surpass single-axis therapies (e.g., GDF15-only inhibitors) by restoring appetite, attenuating inflammation and fatigue, and preserving muscle mass in a population with major unmet need.