Ponsegromab: The new miracle drug for cancer cachexia

The International Consensus Criteria define cachexia as a complex condition involving a body weight loss of more than 5% within 6 months or a reduction in weight exceeding 2% for individuals with a body mass index below 20 or those experiencing sarcopenia.[1] The prevalence of cachexia among patients is currently on the rise. Cachexia is predominantly found in individuals diagnosed with pancreatic, gastric cancers, with subsequent occurrences in those with colon, lung, and prostate cancers, as well as in cases of non-Hodgkin lymphoma. Finite drug therapy options are available for cancer cachexia treatment. Recent studies have shown that megestrol acetate improves body weight and appetite, but the gain in fat and fluid is greater than that in the muscles.[2] When assessing its application, it is crucial to consider the potential adverse effects such as increased mortality, thromboembolism, and its impact on adrenal and androgen function. Anamorelin, an oral ghrelin receptor agonist approved in Japan, successfully increased lean body mass, weight, and appetite. However, it did not improve hand grip strength, leading to the FDA’s decision not to approve it.[3] The raised level of growth differentiation factor 15 (GDF-15) in the bloodstream correlates with the development of cachexia and a decline in survival rates among individuals with cancer. When stress activates this cytokine, it binds to the glial cell-derived neurotrophic factor family receptor alpha-like protein (GFRAL) located in the hindbrain. The GDF-15–GFRAL signaling pathway has been identified as a major mechanism of appetite suppression and weight control, and it is crucial in the progression of cachexia.[4] In a murine Cancer Cachexia (CC) model, a therapeutic monoclonal antibody has been identified to reverse excessive protein catabolism and muscle wasting, thereby enhancing muscle function through this pathway. The promising preclinical advantages underscore GDF-15 as a viable target for therapeutic intervention. Ponsegromab is a highly effective and specifically engineered humanized monoclonal antibody that targets GDF-15 in the bloodstream, thereby blocking its binding with the GFRAL receptor [Figure 1]. A phase 2 clinical trial by Groarke et al. showed encouraging results of ponsegromab on patients with cancer cachexia linked to lung, pancreatic, or colorectal cancer.[5] Patients taking its highest dose showed profound effects on weight, appetite, muscle mass, and level of physical activity. The documented side effects include diarrhea, cancer progression, anemia, hypokalemia, nausea, vomiting, and fever.Figure 1: Mechanism of action of ponsegromab. GDF-15: Growth differentiation factor 15, GFRALThese findings highlight the significance of employing a biomarker-guided approach, a strategy that has largely been neglected in past clinical trials, indicating a forward-looking path for precision medicine in the treatment of cachexia. In conclusion, ponsegromab has been quite successful in combating cancer cachexia; however, it is a complex condition with multiple contributing factors, suggesting that it is unlikely to be effectively managed through a single pathway, as indicated by Groarke et al. To optimize the success of these and other therapeutic interventions, it is crucial to implement a standardized framework for nonpharmacological cachexia management that incorporates elements such as physical activity, a diet rich in protein, and supplements high in energy. The efficacy of ponsegromab should also be assessed in other conditions, in which cachexia is a feature. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.