Plasma Fibrinogen Qualification as a Drug Development Tool in Chronic Obstructive Pulmonary Disease. Perspective of the Chronic Obstructive Pulmonary Disease Biomarker Qualification Consortium.

The COPD Foundation Biomarker Qualification Consortium (CBQC) is a unique public-private partnership established in 2010 between the COPD Foundation, the pharmaceutical industry, and academic chronic obstructive pulmonary disease (COPD) experts with advisors from the U.S. NHLBI and the Food and Drug Administration (FDA). This was a direct response to the 2009 publication of a guidance on qualification of drug development tools by the FDA. Although data were believed to be available from publicly funded and industry-funded studies that could support qualification of several tools, the necessary data resided in disparate databases. The initial intent of the CBQC was to integrate these data and submit a dossier for the qualification. This led to the FDA qualification of plasma fibrinogen as a prognostic or enrichment biomarker for all-cause mortality and COPD exacerbations in July 2015. It is the first biomarker drug development tool qualified for use in COPD under the FDA's drug development tool qualification program. This perspective summarizes the FDA's qualification process, the formation of the CBQC, and the effort that led to a successful outcome for plasma fibrinogen and discusses implications for future biomarker qualification efforts.

Plasma Fibrinogen as a Biomarker for Mortality and Hospitalized Exacerbations in People with COPD.

BACKGROUND: In 2010 the COPD Foundation established the COPD Biomarkers Qualification Consortium (CBQC) as a partnership between the Foundation, the Food and Drug Administration (FDA), and the pharmaceutical industry to pool publicly-funded and industry data to develop innovative tools to facilitate the development and approval of new therapies for COPD. We present data from the initial project seeking regulatory qualification of fibrinogen as a biomarker for the stratification of COPD patients into clinical trials. METHODS: This analysis pooled data from 4 publicly-funded studies and 1 industry study into a common database resulting in 6376 individuals with spirometric evidence of COPD. We used a threshold of 350 mg/dL to determine high vs. low fibrinogen, and determined the subsequent risk of hospitalizations from exacerbations and death using Cox proportional hazards models. RESULTS: High fibrinogen levels at baseline were present in 2853 (44.7%) of individuals with COPD. High fibrinogen was associated with an increased risk of hospitalized COPD exacerbations within 12 months (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.39-1.93) among participants in the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. High fibrinogen was associated with an increased risk of death within 36 months (HR: 1.94; 95% CI: 1.62-2.31) among all participants. CONCLUSIONS: Fibrinogen levels ≥ 350 mg/dL identify COPD individuals at an increased risk of exacerbations and death and could be a useful biomarker for enriching clinical trials in the COPD population.

Epigenetic bystander-like effects of stroke in somatic organs.

Clinical evidence suggests that stroke may lead to damage of somatic organs. This communication of damage is well- established in the case of exposure to genotoxic agents is termed a bystander effect. Genotoxic stress-induced bystander effects are epigenetically mediated. Here we investigated whether stroke causes epigenetic bystander-like effects in the liver, kidney and heart. We found a significant increase in the levels of H3K3 acetylation and H3K4 trimethylation, as well as a decrease in the H3K9 trimethylation in the kidney tissue of stroked rats. Furthermore, here we for the first time show changes in the gene and microRNA expression profile in the kidney tissues of stroked rats, as compared to intact control animals. Interestingly, the observed changes were somewhat similar to those reported earlier in kidney injury, inflammation, and acute renal failure. Our data explain the recent epidemiological evidence for the increased incidence of acute kidney injury post-stroke and provide an important roadmap for the future analysis of the mechanisms and cellular repercussions of the stroke-induced bystander-like effects in distal somatic organs.