Acute Respiratory Distress Syndrome (ARDS) is a devastatingly intense lung inflammatory disorder that annually afflicts more than 1 million individuals world-wide (200,000 cases/year in the U.S.) with an unacceptable mortality rate of 30-40%. Substantial clinical and biological heterogeneity within ARDS phenotypes has greatly impeded therapeutic developments to reduce mortality. All therapies currently employed in ARDS management are ge- neric. The critical care community suffers from a lack of tools that allow identification of ARDS sub-phenotypes and individuals most likely to benefit from novel therapies. Recently, the hyperinflammatory and low inflammatory ARDS sub-phenotypes were identified that markedly differ in natural histories, clinical and biological character- istics, biomarker profiles, responses to positive end-expiratory pressure, ventilator- and organ failure-free days and mortality. ARDS severity (PaO2/FiO2 ratio), the severity of renal or hepatic failure, or the extent of leukocy- tosis failed to distinguish the two phenotypes. As the mortality of the hyperinflammatory phenotype is 3-5 times greater than low inflammatory phenotype, this Phase I STTR will leverage substantial complementary expertise to: i) establish a novel panel of ARDS biomarkers (CRIT-ICU Panel) that stratifies subjects at risk for ARDS into high and low mortality sub-phenotypes; and ii) develop a quantitative platform to allow assessment of these validated biomarkers upon patient entry into the ER or ICU. Our preliminary biomarker data are strong and include 11 ARDS-relevant plasma biomarkers in >250 well-phenotyped ARDS subjects and 70 controls. The targeted biomarkers include cytokine-chemokines (IL-6, IL-8, IL-1b, IL-RA), dual-functioning cytozymes i.e. cy- tokine/intracellular enzymes (macrophage migration inhibitory factor, NAMPT), vascular injury markers (VEGF- A, S1PR3, angiopoietin 2), and the advanced glycosylation end product pathway (HMGB1, soluble RAGE). Spe- cific Aim #1 will apply standard biostatistical approaches as well as novel neural network artificial intelligence analysis of this existing dataset to identify an optimal plasma-derived CRIT-ICU Panel which predicts ICU mor- tality in patients with sepsis or trauma who are at risk for development of respiratory failure and ARDS.
Specific Aim #2 will develop an optimized and highly standardized Predictive Platform for the CRIT-ICU biomarkers iden- tified to be used in the clinical care setting. Finally, Specific Aim #3 will conduct retrospective validation studies of the optimized CRIT-ICU Panel in biobanked samples from 2 large cohorts: an emergency room-ARDS cohort (PETAL Clinical Network, n=800) and a Spanish sepsis-ARDS cohort (n=200). We speculate that unique exper- tise within Aqualung Therapeutics Corp., PAI Life Sciences Inc., InBios International Inc. and the University of Arizona Health Sciences will drive future prospective validation of the CRIT-ICU Panel in patients at risk for ARDS (Phase II STTR) and lead to development of a true Point of Care test to accelerate clinical trial stratification strategies, and development of innovative ARDS therapeutics to reduce mortality in this devastating syndrome.
Acute Respiratory Distress Syndrome (ARDS) is a devastatingly intense lung inflammatory disorder that afflicts more than 1 million individuals world-wide each year (200,000 cases/year in the U.S.) with an unacceptable mortality rate of 30-40%. The tremendous heterogeneity of ARDS has greatly impeded therapeutic developments to address ARDS mortality and all therapies currently employed in ARDS management are generic. The critical care community suffers from a lack of empirical data and tools that would allow identification of ARDS sub- phenotypes and potentially identify individuals most likely to benefit from novel therapies. This Phase I STTR leverages substantial complementary expertise to establish a novel panel of ARDS biomarkers (CRIT-ICU Panel) that will be used to stratify subjects at risk for ARDS into high and low mortality sub-phenotypes and develop a predictive platform to allow assessment of these validated biomarkers upon entry into the ER or ICU. This will accelerate the conduct of clinical trial stratification strategies and lead to more robust innovation in ARDS thera- peutics to reduce mortality in this devastating syndrome.