Pfizer's ponsegromab, a monoclonal antibody targeting growth differentiation factor-15 (GDF-15), has demonstrated positive results in a Phase 2 clinical trial for treating cancer cachexia. The study met its primary endpoint, showing a statistically significant increase in body weight compared to placebo in patients with cancer and elevated GDF-15 levels. These findings, presented at the European Society for Medical Oncology (ESMO) 2024 Congress and published in The New England Journal of Medicine, offer a potential breakthrough for a condition with limited treatment options.
The Phase 2 trial (NCT05546476) involved 187 participants with non-small cell lung cancer, pancreatic cancer, or colorectal cancer, all suffering from cachexia and having elevated serum GDF-15 concentrations (>1500 pg/mL). Patients were administered ponsegromab at doses of 100 mg, 200 mg, or 400 mg, or placebo, subcutaneously every four weeks for a total of 12 weeks. The primary endpoint was the change from baseline in body weight.
Significant Weight Gain Observed
The results showed significant and robust increases in body weight across all ponsegromab doses compared to placebo. Specifically, the 100 mg group saw a 2.02% increase (95% CI, -0.97 to 5.01%), the 200 mg group a 3.48% increase (95% CI, 0.54 to 6.42%), and the 400 mg group a 5.61% increase (95% CI, 2.56 to 8.67%).
Improvements in Cachexia Phenotype
In addition to weight gain, the 400 mg dose group exhibited improvements across multiple domains of the cachexia phenotype. These included enhanced appetite, reduced cachexia symptoms, increased physical activity, and a greater skeletal muscle index. According to Jeffrey Crawford, M.D., George Barth Geller Professor for Research at Duke Cancer Institute, and principal investigator, these findings offer hope for a targeted treatment for patients, addressing weight loss, functional decline and poor outcomes associated with cachexia.
Safety and Tolerability
Ponsegromab was generally safe and well-tolerated across all dose levels. Treatment-related adverse events occurred in 8.9% of patients taking placebo and 7.7% of patients taking ponsegromab, indicating a favorable safety profile.
Future Development
Based on these promising Phase 2 results, Pfizer is in discussions with regulators to initiate registration-enabling studies in 2025. Charlotte Allerton, Head of Discovery and Early Development at Pfizer, emphasized that these results provide strong evidence of interrupting a critical driver of cachexia, GDF-15. Ponsegromab is also being investigated in a Phase 2 study in patients with heart failure and elevated serum GDF-15 concentrations (NCT05492500).
About Cancer Cachexia
Cachexia is a debilitating metabolic condition affecting approximately 9 million people worldwide. It is characterized by weight and muscle loss, reducing patients' ability to tolerate treatments for underlying chronic diseases like cancer and heart failure, and severely impacting their quality of life. In cancer patients, cachexia can diminish the efficacy of cancer treatments and contribute to decreased survival rates, accounting for up to 30% of cancer-related deaths. Currently, there are no FDA-approved treatments for cachexia, highlighting the unmet medical need this drug aims to address.
