Ponsegromab Shows Sustained Weight Gain in Cancer Cachexia Patients Over 64-Week Extension Study
Key Insights
Ponsegromab treatment over 64 weeks resulted in sustained body weight improvements and robust suppression of GDF-15 (search) in cancer-associated cachexia (search) patients, with mean weight gain reaching 5.18 kg by week 64.
Patients initially on placebo gained weight after transitioning to ponsegromab but achieved lower overall gains compared to those continuously treated with the monoclonal antibody.
The open-label extension demonstrated a favorable safety profile with treatment-related adverse events occurring in less than 5% of patients and limited to grade 1-2 severity.
Ponsegromab, a humanized monoclonal antibody targeting growth differentiation factor 15 (GDF-15 (search)), demonstrated sustained efficacy in treating cancer-associated cachexia (search) over a 64-week treatment period, according to results from an open-label extension study presented at the 2025 ESMO Congress in Berlin.
The extension study showed progressive weight gains throughout the 52-week open-label phase, with patients achieving a mean weight increase of 5.18 kg by week 64, representing a 9.35% increase from baseline. Dr. Jeffrey Crawford, a medical oncologist at Duke Cancer Center (search), emphasized that patients initially randomized to placebo benefited from weight gain upon transitioning to ponsegromab, although their absolute gains remained lower than those continuously treated.
Addressing an Unmet Medical Need
Cancer-associated cachexia (search) remains a common complication in oncology with no currently approved pharmacologic therapies in the United States or Europe. GDF-15 (search), a stress-induced cytokine, has been implicated in cachexia pathogenesis through its interaction with the GFRAL (search) receptor in the hindbrain. Ponsegromab functions as a potent, highly selective humanized monoclonal antibody that binds GDF-15, preventing its signaling through GFRAL.
Study Design and Patient Population
The randomized phase 2 trial comprised two parts. Part A was a 12-week double-blind, randomized, placebo-controlled study involving patients with non-small cell lung cancer (search), pancreatic cancer (search), or colorectal cancer (search) meeting Fearon criteria for cachexia. Eligible patients had elevated circulating GDF-15 (search) levels above 1,500 pg/mL, ECOG performance status of 3 or less, and life expectancy of 4 months or more.
During Part A, patients were randomized to receive placebo or ponsegromab at doses of 100 mg, 200 mg, or 400 mg subcutaneously every four weeks for three doses. Part B consisted of a 52-week open-label extension where all eligible patients received ponsegromab 400 mg subcutaneously every four weeks through week 64.
Of 281 patients screened, 187 were randomized to Part A, and 117 patients entered Part B. Baseline demographics showed a median age of 68 years, with 35.9% female patients and median BMI of 20.1 kg/m². Cancer types included non-small cell lung cancer (search) (44.4%), colorectal cancer (search) (29.1%), and pancreatic cancer (search) (26.5%). Cachexia severity at baseline included 38.5% of patients with 5-10% weight loss and 43.6% with 10% or more weight loss in the preceding six months.
Sustained Weight Gain and GDF-15 Suppression
The extension study demonstrated progressive weight gains over the 52-week open-label period. At week 12, reflecting Part A treatment assignment, the overall mean increase was 1.26 kg, rising to 5.18 kg at week 64. When stratified by Part A assignment, patients initially randomized to placebo experienced weight loss at week 12 but gained weight following initiation of open-label ponsegromab 400 mg, though achieving less overall gain than patients continuously treated with ponsegromab from Part A.
"We note that the placebo group, across all those time points, tends to gain less weight than the group initially assigned ponsegromab," Crawford explained. "We see an increase across all groups in weight with open-label ponsegromab 400 mg, but the initial placebo group lags behind."
GDF-15 (search) suppression proved robust and sustained throughout the study period. At week 12, placebo patients demonstrated rising GDF-15 levels, whereas ponsegromab-treated groups exhibited 55% to 97% reductions. After transitioning to open-label ponsegromab 400 mg, all patients achieved a median 97% decrease in GDF-15, maintained through week 64, regardless of initial treatment assignment.
Safety Profile
Treatment-emergent adverse events were common, occurring in 84.2% of patients, but were largely attributed to underlying malignancy, concomitant therapies, and comorbidities. Grade 1-2 adverse events occurred in 34.2% of patients, grade 3-4 in 29.8%, and grade 5 events in 20.2%. Serious adverse events affected 43.9% of patients, with 24.6% permanently discontinuing study interventions.
Importantly, treatment-related adverse events were rare, occurring in less than 5% of patients and limited to grade 1-2 severity. No deaths were considered related to ponsegromab treatment, supporting the drug's favorable safety profile.
Clinical Implications and Next Steps
The sustained weight gain and GDF-15 (search) suppression observed over 64 weeks support ponsegromab's potential as the first approved therapy for cancer-associated cachexia (search). The results demonstrate that continuous treatment provides superior outcomes compared to delayed initiation, emphasizing the importance of early intervention in cachexia management.
These findings support ongoing evaluation in a phase 2b study of ponsegromab in patients with metastatic pancreatic cancer (search) receiving first-line chemotherapy. This study is designed to define optimal dosing for a subsequent pivotal phase 3 trial, incorporating both cachexia-specific and treatment-related outcomes.