SMART Use of Biologics in Chronic Rhinosinusitis with Nasal Polyposis

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common condition characterized by persistent sinonasal mucosal inflammation resulting in visible polyps, cardinal symptoms such as nasal congestion and loss of smell, and a significant reduction in quality of life. The development of biologic medications over the last 5 years has revolutionized the treatment of CRSwNP. However, data from industry clinical trials does not show universal improvement and ideal control of disease across all patients with CRSwNP. This should not be surprising in light of our recent data showing up to 40% of patients with CRSwNP do not have a classic Type 2 endotype. As expected, phase III clinical trials were designed primarily to achieve regulatory approval and broad indications. The result is that we have no way of knowing which specific biologic would be the best option for any given patient, nor do we know whether biomarkers can be used to predict response to biologics. These persistent gaps in understanding have resulted in an unfortunate treatment paradigm where clinicians empirically choose a biologic and wait to see if the patient benefits. Considering the extreme cost of biologic medications and need for long-term treatment, this non-selective utilization of a selective medication represents a current clinical problem and unmet scientific need. Therefore, the primary objective of the proposed study is to compare clinical outcomes across specific biologics. Furthermore, we hypothesize that biomarkers can be used to identify patients most likely to improve on biologic therapy. These hypotheses will be tested via a pragmatic, multi-arm, randomized clinical trial. Patients with CRSwNP who have elected to pursue biologic therapy will be enrolled and rigorous baseline data obtained including sinonasal mucus for biomarker assessment. Patients will be randomized 1:1:1 to one of three treatment arms (dupilumab, omalizumab, or mepolizumab). The primary outcome is change in sinonasal quality of life (SNOT-22) after 24 weeks of treatment. Key secondary outcomes include change in nasal congestion score, polyp grade, and olfaction after 24-weeks of treatment. An additional analysis will determine whether changed in the primary outcome at 24- weeks can be predicted using mucus biomarkers collected at baseline in the clinic setting. Successful completion of this trial will help answer some of the most pressing clinical questions related to biologics and CRSwNP. Specifically, findings will inform whether any one biologic has superior outcomes to another, whether clinicians can identify patients at baseline who are most likely to improve on biologic therapy, and finally whether mucus biomarkers can predict a patient’s response to biologic therapy. Project Number: 1U01AI181696-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: TIMOTHY SMITH (+2 co-PIs) | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $1,498,642 | Activity Code: U01 | Study Section: Special Emphasis Panel[ZAI1 PT-I (J1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1U01AI18169601A1