Neuromodulation of the Gut-Brain Axis to Treat Cancer-Associated Cachexia

Abstract public domain (NIH RePORTER)

Cancer-associated cachexia (CAC) is a systemic syndrome defined by substantial weight loss or skeletal muscle atrophy. The condition decreases quality of life, leads to higher mortality rates, and reduces tolerance for cancer treatments such as radio- and chemotherapy. CAC affects an estimated 0.5-1% of the global population, including 1.3 million Americans, and is ultimately responsible for up to half of all cancer deaths. CAC has no effective clinical treatment, despite significant efforts surrounding nutritive support, physical therapy, anti-inflammatory drugs, and appetite agonists. Fundamentally, existing treatment paradigms fail to reverse the underlying metabolic pathology which drives CAC and produces downstream wasting. Vagus nerve stimulation (VNS) provides a promising means to perturb aberrant signaling along the gut-brain axis; this therapy is FDA approved for a variety of applications but has never been applied to CAC. Direct vagal innervation of the digestive tract, brown adipose, kidneys, liver, and pancreas provide known pathways related to ingestion, appetite, nutrient sensing, digestion, metabolism, inflammation, and glucose homeostasis which are disrupted in CAC patients. Promising preliminary results in two gold-standard CAC models in mice suggest this therapy has significant clinical promise for this fatal condition with no existing treatments. OnVagus has developed a non-invasive, transcutaneous VNS device and has established preclinical safety and successful vagal neuromodulation in swine and voluntary human subjects. In this SBIR Fast-track, an interdisciplinary partnership between bioengineers at OnVagus and clinicians at the University of Texas MD Anderson Cancer Center will utilize a transcutaneous vagal neuromodulation device to non-invasively assess benefits in pancreatic cancer patients. This first of its kind project will provide the pivotal clinical data that serves as a basis for de novo regulatory clearance and device labeling. In Phase 1, we will characterize the improved device using a porcine large animal model and test the device on 10 patients under clinical supervision to confirm safety and functionality, providing clinician and patient usage feedback and safety testing in a clinical setting. In Phase 2 we will perform randomized pilot clinical trials on 120 patients, establishing efficacy of transcutaneous VNS for metastatic pancreatic cancer in combination with standard-of-care therapy, assessing outcomes and progression compared to placebo control group (device with no therapeutic electrical output). Successful completion will serve as the basis for a de novo application with CDRH, supporting the development and commercialization of the first ever clinically effective treatment for CAC.

Public health relevance public domain (NIH RePORTER)

Cancer-associated cachexia (CAC) is a fatal condition affecting up to 1% of the global population, including 1.3 million Americans, and is responsible for one-third of all cancer-related deaths. Despite its impact, no approved therapies exist to halt or reverse CAC, leaving patients unable to continue cancer treatment. In this study, OnVagus and MD Anderson Cancer Center partner to launch the first clinical trials evaluating non-invasive vagus nerve stimulation (VNS) therapy for pancreatic cancer patients at risk of severe CAC, offering new hope based on strong preclinical data.