Ponsegromab Demonstrates Sustained Weight Gain and GDF-15 Suppression in Cancer-Associated Cachexia
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A novel treatment, ponsegromab, has shown promising long-term benefits for patients suffering from cancer-associated cachexia, a debilitating condition characterized by weight loss and muscle wasting. Results from a 64-week study, presented at the 2025 ESMO Congress in Berlin, Germany, indicate sustained improvements in body weight and significant suppression of growth differentiation factor 15 (GDF-15), a key cytokine driving the condition, regardless of initial treatment assignment.
Addressing an Unmet Need in Cancer Care
Cancer-associated cachexia remains a significant and often overlooked complication of cancer, impacting quality of life and treatment outcomes. Currently, there are no approved pharmacological therapies specifically targeting cachexia in the United States or Europe, highlighting the urgent need for effective interventions. GDF-15 plays a central role in the development of cachexia by interacting with the GFRAL receptor in the brain, and ponsegromab is designed to interrupt this process. As explained by a presenter at the ESMO Congress, ponsegromab is a “potent, highly selective humanized monoclonal antibody that binds GDF-15, preventing its signaling through GFRAL.”
Study Design and Key Findings
The data presented builds upon a previously reported 12-week double-blind study (NCT05546476) and encompasses a 52-week open-label extension. The randomized phase 2 trial involved 187 patients with non-small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer (CRC) experiencing cachexia, defined by the Fearon criteria, and elevated GDF-15 levels. Patients were initially randomized to receive either placebo or ponsegromab at varying dosages (100mg, 200mg, or 400mg) every four weeks.
The study was divided into two parts: a 12-week double-blind, placebo-controlled phase (Part A), followed by a 52-week open-label extension (Part B) where all participants received ponsegromab 400mg every four weeks. The primary endpoint of Part A was change in body weight at week 12, while Part B focused on evaluating longitudinal changes in body weight, GDF-15 levels, and safety over the extended treatment period.
Overall, patients experienced progressive weight gains during the 52-week extension, with a mean increase of 5.18 kg (SD, 5.92) at week 64, representing a 9.35% increase from baseline. Notably, even patients who initially received placebo and subsequently transitioned to ponsegromab experienced weight gain, although to a lesser extent than those continuously treated with the drug. “We note that the placebo group…tends to gain less weight than the group initially assigned ponsegromab,” a lead investigator emphasized.
GDF-15 suppression was also remarkably consistent. While placebo patients showed rising GDF-15 levels at week 12, those treated with ponsegromab experienced reductions ranging from 55.1% to 97.6%. After switching to open-label ponsegromab 400mg, all patients achieved a median decrease in GDF-15 of approximately 97%, maintained through week 64.
Safety and Tolerability Profile
Ponsegromab demonstrated a consistent and tolerable safety profile throughout the 64-week study. Treatment-emergent adverse effects (TEAEs) were common (84.2%), but largely attributed to the underlying malignancy, concurrent therapies, and existing patient comorbidities. Importantly, treatment-related TEAEs were rare (4.4%) and limited to grade 1 and 2 severity, with no treatment-related deaths reported.
Next Steps: Targeting Pancreatic Cancer
These encouraging results are driving further investigation of ponsegromab in a phase 2b study focusing on patients with metastatic pancreatic cancer receiving first-line chemotherapy. This study aims to determine the optimal dosage for a subsequent, pivotal phase 3 trial, incorporating both cachexia-specific and treatment-related outcomes.
The ongoing research with ponsegromab offers a beacon of hope for individuals battling cancer-associated cachexia, potentially improving their quality of life and treatment tolerance.
Reference: Crawford J, Groarke JD, Collins SM, et al. Efficacy and safety of ponsegromab in patients with cancer-associated cachexia: Results from the open-label extension of a randomized, placebo-controlled. Presented at: ESMO 2025 Congress; October 17-21, 2025; Berlin, Germany. LBA102.
