Ponsegromab increases weight in patients with cancer cachexia

Use of ponsegromab is associated with increased weight gain and reduced cachexia symptoms in patients with cancer cachexia, according to results of a phase II, randomized, double-blind study.

Cachexia is common among patients with multiple forms of cancer and is characterized by weight loss, muscle wasting, reduced quality of life, functional impairment, and diminished overall survival. [J Cachexia Sarcopenia Muscle 2016;7:507-509; Lancet Oncol 2011;12:489-495] Growth differentiation factor 15 (GDF-15) is a stress-induced cytokine involved in body weight regulation, which induces cachexia in animal models, while its inhibition alleviates this phenotype. [Cell Rep 2023;42:111947-111947; J Cachexia Sarcopenia Muscle 2023;14:1441-1453] Ponsegromab is a humanized monoclonal antibody inhibitor of GDF-15, which has shown improvements in weight, appetite, and physical activity, along with lowering of serum GDF-15 levels in a small, open-label, phase Ib study in patients with cancer cachexia. [Clin Cancer Res 2024;30:489-497]

In the present phase II study, 187 patients (median age, 67 years; median weight, 54.8 kg; women, 37 percent; Asian, 37 percent) with cancer cachexia and an elevated serum GDF-15 level of ≥1,500 pg per milliliter were randomized in a 1:1:1:1 ratio to receive ponsegromab at a dose of 100 mg, 200 mg, or 400 mg, or placebo, administered subcutaneously Q3W for 12 weeks. [N Engl J Med 2024;doi:10.1056/NEJMoa2409515]

At 12 weeks, patients who received ponsegromab had significantly greater weight gain than those in the placebo group, with a median between-group difference of 1.22 kg in the 100 mg group (p<0.05), 1.92 kg in the 200 mg group (p<0.05), and 2.81 kg in the 400 mg group (p<0.05). “The effect of ponsegromab on weight was consistent across various sensitivity analyses, and differences in body weight relative to placebo were evident at 8 weeks after two doses of ponsegromab,” noted the researchers.

Ponsegromab was associated with weight gain in patients with even the most severe weight loss. Half of the patients in the trial had a BMI-adjusted weight loss of grade 4, which is associated with more refractory cachexia and shortest survival. [J Clin Oncol 2015;33:90-99] “Nevertheless, these patients had robust weight gain vs placebo [difference, 5.20 kg] in response to ponsegromab. These results challenge the concept of refractory cachexia and suggest that even patients with advanced cachexia may benefit from ponsegromab,” commented the researchers.

Patients in the ponsegromab 100 mg and 400 mg groups had improvements in Functional Assessment of Anorexia Cachexia Treatment–Anorexia Cachexia Subscale (FAACT-ACS) and FAACT–5-Item Anorexia Symptom Scale scores vs patients on placebo, while there were no material differences in these scores between the ponsegromab 200 mg and placebo groups. The latter finding may be due to a higher percentage of patients in the ponsegromab 200 mg group reporting no appetite loss at baseline than in the other groups.

Similar percentages of patients in the ponsegromab and placebo groups reported adverse events (AEs) of any cause (67–74 and 80 percent, respectively). AEs deemed by the investigators to be related to ponsegromab or placebo were reported in 4–11 vs 9 percent of patients in the respective groups. Serious AEs of any cause occurred in 22–40 vs 24 percent of patients. Increased systolic blood pressure (difference vs placebo, 9.6 mm Hg) was observed in the ponsegromab 400 mg group at 12 weeks, but no such difference was noted in the other ponsegromab groups.

“All ponsegromab doses were considered to be safe and had a side-effect profile similar to that of placebo,” concluded the researchers. “Collectively, these results highlight the potential for ponsegromab as a targeted therapy for cancer cachexia.”