R James White III, M.D., Ph.D.

The University of Rochester is a nationally accredited PHA Comprehensive Care Center, and we provide evaluations for patients with echo estimated pulmonary hypertension. We take care of ~300 patients with WHO Group 1 classified Pulmonary Arterial Hypertension. I was a lead enroller and study author in the labeling trials for tadalafil (PHIRST), oral treprostinil (Freedom-M), and the initial combination Ambition study. I chair the Freedom-EV steering committee and am leading the ongoing global development efforts for oral treprostinil in WHO Group 1. We participated actively in the Reveal registry, and I am associate medical director for Bill Nichols' NIH funded PAH Biobank. We are the lead nationwide enrollers for the NIH funded study of rituxan in scleroderma PAH, and we are making active contributions to Reata's studies of bardoxolone. We use subcutaneous treprostinil (Remodulin, more than 150 patients over the years), inhaled Tyvaso, ambrisentan, tadalafil, macitentan, selexipag, and riociguat in combinations best tailored to a particular patient's needs. We provide a strong link to surgical centers at Massachusetts General and Allegheny General for our patients with chronic thromboembolic pulmonary hypertension.

I am grateful for the opportunity to serve as steering committee leadership in drug development projects with United Therapeutics (oral treprostinil) and PhaseBio (VIP analogue PB1046). I also serve as a consultant providing development advice to Reata, Gilead, Bayer, and Celtaxsys. I chair the DSMB for the first randomized, placebo-controlled trial of genetically-modified, endothelial progenitor cells led by colleagues in Canada (sponsor, Northern Therapeutics).

The overall goal of my bench laboratory is to do better preclinical testing of potential novel treatment options for pulmonary arterial hypertension. Our current approach is with a rat model that recapitulates the histopathology, severe hemodynamic alterations, and right ventricular heart failure seen in advanced human disease. This rat model employs pneumonectomy (promotes contralateral lung growth) and endothelial injury (low dose monocrotaline) to cause lethal pulmonary hypertension in about 4 weeks. Our animals die earlier with a more severe phenotype, and we presented the first report of proliferative, plexiform-like lesions in 2004. We have developed a novel CT angiography to assess for vascular pruning during disease progression, and we have become expert at evaluating RV size and function with echo. We have also utilized telemetry techniques to measure pressure in awake, behaving animals. Our main recent contribution has been to establish a model severe enough that we can test new therapy approaches in animals treated with today's FDA approved agents. We believe that this sort of preclinical testing will provide the best evidence to move compounds into the clinic. Deb Haight, LVT, leads the lab work.

We hypothesize that tissue factor (the membrane bound glycoprotein which initiates coagulation) is an important contributor to disease progression, and we are actively testing small molecule inhibitors of tissue factor and thrombin as novel therapies in this devastating disease.