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Vascular and Endothelial Biomarkers in PAH
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Dr. Ioana Preston reviews the results of 'Oral Treprostinil in Combination with Endothelin Receptor Antagonist and/or PDE-5 Inhibitor for the treatment of PAH (FREEDOM-C2)', presented at the 2016 CHEST Annual Meeting. The study objective was to determine whether in patients with PAH, vascular biomarkers correlate with 6-minute walk distance and NY Heart Association Functional Class.

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Good day. This is Ioana Preston. I am the director of the pulmonary hypertension center at Tufts University School of Medicine in Tufts Medical School. Today I will be presenting the vascular and endothelial biomarkers in pulmonary arterial hypertension study that was presented at CHEST conference in 2016.

We know that vascular mediators are intimately involved in the pathogenesis of pulmonary arterial hypertension with a resultant of endothelial dysfunctions, small muscle cell proliferation and hypertrophy as well as adventitial derangement. We really don't know as of today what is the clear contribution of each vascular mediator to the derangements that we see in patients with pulmonary arterial hypertension. There are some preliminary reports that suggest that mediators such as VEGF, or vascular endothelial growth factor, and its receptor, VEGF receptor, as well as platelet-derived growth factor, PDGF and its receptor, and epidermal growth factor and its receptor have been altered in the lesions of patient with pulmonary arterial hypertension. Therefore, our study objective was to understand and to determine whether in patients with pulmonary arterial hypertension vascular biomarkers correlate with markers of disease severity such as six-minute walk distance and New York Heart Association functional class.

We looked at patients with PAH who were enrolled in the clinical trial with oral Treprostinil in combination with an endothelial receptor antagonist and/or a phosphodiesterase-5 inhibitor for the treatment of PAH, the FREEDOM-C2 trial. The trial was a multi-center, randomized, placebo-controlled 16-week clinical trial that tested the efficacy of oral Treprostinil. The trial was followed by an open-label extension trial. The trial was supported by United Therapeutics. We obtained blood and we measured biomarkers at baseline and at 16 weeks at the end of the randomized portion of the trial and we looked at correlations between baseline biomarkers and baseline six-minute walk distance and New York Heart Association functional class. We also performed a multivariate linear regression model to assess any potential associations between baseline biomarkers and changes in six-minute walk distance from baseline to 16 weeks. The models were adjusted for age, sex, etiology of PAH and treatment arm.

310 subjects were enrolled in the FREEDOM-C2 trial. Out of these, 178 subjects had biomarkers measured. Among those, 83 subjects were in the oral treprostinil arm and 95 subjects were in the placebo arm.

Baseline characteristics of patients in whom biomarkers were evaluated showed a preponderance of female sex and the fact that the majority of patients had idiopathic or familial PAH. One-third of patients had connective tissue disease associated PAH. Patients who were symptomatic at baseline with a significant decrease in six-minute walk distance of around 300 meters on an average at baseline. The baseline characteristics of the patients studied in this protocol were very similar to the entire cohort enrolled in the FREEDOM-C2 trial.

When we looked at different biomarkers and their correlation with baseline New York Heart Association functional class, we were not able to show any correlations between a serologic biomarkers and functional class. On the contrary, we found interesting associations between several biomarkers of vascular origin and six-minute walk distance at baseline. For example, there was an indirect association between Von Willebrand factor and six-minute walk distance. There was a similar negative association between VCAM-1 and six-minute walk distance. Similarly, there was a correlation between six-minute walk distance and resistance and lastly, a positive correlation between six-minute walk distance and endothelial growth factor receptor, or EGFR.

When we looked at multivariate models for change in six-minute walk distance, we did not find any correlation between any of the vascular endothelial factors measured in change in six-minute walk. We need to acknowledge the limitations of our sub-study that may have introduced a selection bias because not all centers participating in the large trial measured blood sample for this particular project and the fact that the sample size was small, so a type one or two error could have been introduced.

In conclusion, in FREEDOM-C2 we found weak but statistically significant correlation between six-minute walk distance at baseline and Von Willebrand factor VCAM-1 resistant and EGFR levels. None of the biomarkers measured correlated with New York Heart Association functional class and we also did not find any association between change in six-minute walk distance and the biomarker level.

What I think is mostly important is the fact that we need to acknowledge that we do not have good biomarkers to assess disease severity and progression in PAH and continue studies to look for biomarkers that have a plausible physiologic and pathophysiologic mechanism that may contribute to the disease process is very important.

This study, although it showed weak signals, that there may be associations between vascular markers of endothelial injury and the disease severity in PAH, it also showed us that it is possible to undergo biomarker studies and we should continue to look for a search in understanding the disease process and better diagnosis and assessment of these patients with non-invasive measures such as biomarkers.

Thank you for listening.