What type of study is this?

This is a Pre-Registered Trial study.

January 14, 2026

Efficacy and safety of ponsegromab in patients with colorectal cancer and cachexia: A subgroup analysis of the PROACC-1 phase 2 study.

Key Points

This research aims to evaluate the efficacy and safety of ponsegromab in patients with colorectal cancer and cachexia.
Phase 2, randomized, double-blind trial of ponsegromab versus placebo.
Patients with colorectal cancer and cachexia with elevated GDF-15 were randomized to different ponsegromab doses or placebo.
The primary endpoint was the change in body weight after 12 weeks.
54 participants had colorectal cancer, with significant body weight gain in ponsegromab groups compared to placebo.
Adverse events were more frequent in placebo-treated patients, highlighting ponsegromab's safety profile.
Gastrointestinal-related adverse events occurred less frequently in ponsegromab-treated participants.

Abstract

110 Background: Ponsegromab is a monoclonal antibody that inhibits growth differentiation factor 15 (GDF-15), a circulating cytokine implicated in cachexia. Here, we report the body weight and safety findings from the subset of participants with colorectal cancer (CRC) in a phase 2, randomized, double-blind trial of ponsegromab versus placebo in patients with cancer cachexia (PROACC-1; NCT05546476). Methods: Patients with cancer, cachexia, and elevated serum GDF-15 (≥1500 pg/mL) (n=187) were randomized 1:1:1:1 to subcutaneous ponsegromab (100, 200, 400 mg) or matching placebo every 4 weeks for 12 weeks. The primary endpoint was a change from baseline (CFB) in body weight at 12 weeks. Safety and tolerability were key secondary endpoints. Results: Overall, 54 participants (28.9% of the overall study population) had CRC (mean age 65.1±11.9 years; 61.1% male; 81.5% stage IV). Baseline mean body weight was 56.5±13.3 kg; 51.9% and 48.1% had a body mass index <20 kg/m 2 and body weight loss over prior 6 months of ≥10%, respectively. Overall, the median GDF-15 level was 6468 (interquartile range 4106, 10052) pg/mL. Dose-responsive increases in body weight were observed at 12 weeks in ponsegromab groups relative to placebo, reaching statistical significance in the 200- and 400-mg ponsegromab groups (Table). All-causality and treatment-related adverse events (AEs) occurred in 60.5% and 5.3% of ponsegromab-treated patients and 81.3% and 6.3% of placebo-treated patients, respectively. Gastrointestinal-related all-causality AEs occurred less frequently in ponsegromab-treated versus placebo participants (34.2% vs 62.5%), including nausea (0% vs 18.8%), vomiting (2.6% vs 25.0%), and diarrhea (5.3% vs 18.8%). Conclusions: Among patients with CRC, cachexia, and elevated GDF-15 levels, GDF-15 inhibition with ponsegromab through 12 weeks resulted in body weight gain and was generally well tolerated. Clinical trial information: NCT05546476 . Change from baseline in body weight at Week 12, kg N n Observed Mean (SD) LS Mean* (90% CI) LS Mean* Difference from Placebo (90% CI) 1-sided p -value a Placebo 16 12 -1.24 (1.98) -1.59(-3.26, 0.07) - - Ponsegromab 100 mg 13 11 +0.54 (3.78) -0.29(-1.96, 1.39) +1.31(-1.05, 3.67) 0.1804 Ponsegromab 200 mg 10 8 +0.88 (4.80) +1.55(-0.48, 3.57) +3.14(0.50, 5.77) 0.0253 Ponsegromab 400 mg 15 8 +4.51 (4.66) +3.37(1.51, 5.23) +4.96(2.46, 7.46) 0.0006 N: number of participants at baseline. n: number of participants with change from baseline values at Week 12. a Modeled LS means, differences and confidence intervals are from a mixed model repeated measures analysis. CI, confidence interval; LS, least squares; SD, standard deviation.

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