Pfizer's investigational monoclonal antibody, ponsegromab, has shown promising results in a Phase 2 clinical trial for treating cancer cachexia. The study, which involved 187 participants with non-small cell lung cancer, pancreatic cancer, or colorectal cancer, met its primary endpoint of change from baseline in body weight compared to placebo.
The results, presented at the European Society for Medical Oncology (ESMO) 2024 Congress and published in The New England Journal of Medicine, indicate that ponsegromab could offer a significant benefit to patients suffering from this debilitating condition. Cachexia, a wasting syndrome characterized by weight loss, muscle atrophy, fatigue, and decreased appetite, affects a large proportion of cancer patients and contributes to decreased survival rates.
Phase 2 Trial Details
The Phase 2 trial (NCT05546476) enrolled patients with cancer cachexia and elevated serum GDF-15 concentrations (>1500 pg/mL). Participants were randomized to receive either ponsegromab (100 mg, 200 mg, or 400 mg) or placebo subcutaneously every four weeks for 12 weeks. The primary endpoint was the change from baseline in body weight. Secondary endpoints included measures of appetite, cachexia symptoms, physical activity, and lumbar skeletal muscle index (LSMI).
Significant Weight Gain and Improved Outcomes
The study demonstrated significant and robust increases in body weight after 12 weeks across all doses of ponsegromab. Specifically, the 400 mg group showed a 5.61% mean increase in body weight (95% CI, 2.56 to 8.67%) compared to placebo. Improvements were also observed in multiple domains of the cachexia phenotype, including appetite, cachexia symptoms, physical activity, and skeletal muscle index.
According to Dr. Jeffrey Crawford, principal investigator and George Barth Geller Professor for Research at the Duke Cancer Institute, "This study showed us those who received ponsegromab had improvement in body weight, muscle mass, quality of life, and physical function. These findings offer hope that a breakthrough in targeted treatment is potentially on the horizon for our patients."
Safety and Tolerability
Ponsegromab was generally safe and well-tolerated. Treatment-related adverse events occurred in 7.7% of patients taking ponsegromab compared to 8.9% of patients taking placebo. No clinically significant adverse trends were noted with ponsegromab administration.
Mechanism of Action
Ponsegromab is a monoclonal antibody that targets growth differentiation factor-15 (GDF-15), a cytokine implicated in the pathogenesis of cachexia. By blocking GDF-15, ponsegromab aims to interrupt a critical driver of cachexia, potentially improving body weight, muscle mass, and overall quality of life for patients.
Future Development
Based on these positive results, Pfizer is discussing late-stage development plans with regulators with the goal of starting registration-enabling studies in 2025. Ponsegromab is also being investigated in a Phase 2 study in patients with heart failure and elevated serum GDF-15 concentrations (NCT05492500).
Charlotte Allerton, Head of Discovery and Early Development at Pfizer, stated, "These results provide strong evidence that we have unlocked a mechanism to interrupt a critical driver of cachexia, GDF-15, which has the potential to impact patients with cancer cachexia and other life-threatening conditions."
