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Positive Phase III Results Reported for Anti-Cancer Agent Xilonix
Positive interim results have been reported from an ongoing, fast-tracked phase III study of the anti-cancer agent Xilonix, a human monoclonal antibody therapy.
The treatment is being evaluated in patients with advanced colorectal cancer, in whom the disease is further complicated by cachexia. The study’s primary endpoint is overall survival in Xilonix-treated patients compared with a control population that received only palliative therapy for cachexia.
An interim analysis was recently conducted of the 40 patients who have entered the study to date. More than half of these patients have succumbed to disease, allowing a preliminary analysis of study endpoints. At the time of the analysis, patients receiving Xilonix had a hazard ratio for the risk of death of 0.33 (P = 0.11) compared with the control subjects. This hazard ratio suggested a marked trend for improved survival in the Xilonix-treated group compared with the controls.
The unscheduled interim analysis took place during a halt in the study for protocol amendments, which the drug’s developer (XBiotech) says are intended to correct what are believed to be barriers to patient enrollment. The company reports it is collaborating with the FDA on revisions that will ensure that the protocol remains suitable for a biologic licensing application. Patients are expected to be enrolled under the revised protocol as early as October of this year.
Xilonix is a first-in-class “true human” monoclonal (IgG1k) antibody that neutralizes the biologic activity of interleukin (IL)-1-alpha. XBiotech uses the term “true human” to differentiate Xilonix from other antibodies, such as so-called “fully human,” that are not derived from a mature human antibody sequence. Unlike previous generations of humanized or fully human antibodies, Xilonix was cloned from an affinity-matured, human immune response with no in vitro sequence modifications to improve its binding affinity, XBiotech says. In vitro sequence modifications cause immunogenicity, which leads to infusion reactions, the risk of anaphylaxis, and the creation of anti-product antibodies.
Neutralizing IL-1-alpha activity with a monoclonal antibody is believed to have broad antineoplastic effects. Depending on the site of action, IL-1-alpha mediates a number of crucial physiologic processes related to the response to injury (e.g., tumor growth). At the site of injury (such as in the microenvironment of the growing tumor), IL-1-alpha induces the expression of vascular growth factors, including vascular endothelial growth factor (VEGF), thereby mediating growth and angiogenesis. IL-1-alpha also induces the expression of matrix metalloproteinases, which in turn have pleiotropic activities, including tissue-matrix breakdown, regulation of Fas receptor-mediated apoptosis, and inflammation.
Through its effect on platelets, IL-1-alpha also regulates interactions between endothelial cells and leukocytes, thereby driving the activation of vascular endothelial cells and the transendothelial migration of inflammatory cells into the tumor microenvironment. Similarly, tumor platelet micro-emboli formed between platelets and circulating tumor cells provide tumor cells with an enhanced ability to migrate from the vasculature into the tissues, resulting in new metastasis. Finally, IL-1-alpha links these tumor processes to metabolic dysregulation by signaling an injury response through IL-1 receptors on pro-opiomelanocortin (POMC) neurons, which interdigitate the endothelial microvasculature of the hypothalamus.