Abstract
Currently, clinical trials in pulmonary hypertension (PH) are limited by the absence of mechanistic arms, by weak end points, by failure to capture biological material, and by the inability to restudy data. Clinical studies in PH would be markedly enhanced by a consortium approach that utilizes the expertise of academic medicine, the therapeutic initiatives of the pharmaceutical industry, and study design from funding agencies interested in biological mechanisms. New approaches to PH are emerging from basic studies of signaling, management of the genome, and preservation of metabolic function and from testing of newer molecules that have efficacy in oncologic and inflammatory illnesses.
Primary therapies for PH are limited to 4 main mechanisms: prostacyclins, which vasodilate but may have a beneficial effect on right ventricular (RV) function; endothelin receptor blockade; augmentation of cyclic guanosine monophosphate, either through phosphodiesterase-5 antagonism or stimulation of soluble guanylate cyclase; and calcium channel blockade for the 5%–8% of vasodilator responders. There is a pressing need for therapies with newer mechanistic targets and for a collective approach to clinical designs that will allow for faster testing and development of cohort identification. Collaborative approaches in oncology might serve as a model going forward. Currently, the multiple etiologies leading to a PH phenotype are classified together for purposes of clinical trials, which undoubtedly leads to false-negative data. The failure of imatinib might represent a failure to appropriately phenotype patients who could benefit from tyrosine kinase inhibition.
The Pulmonary Vascular Research Institute (PVRI) held the first annual Drug Discovery and Development Symposium for Pulmonary Hypertension (DDDS-PH) in Bethesda, Maryland, on July 14–15, 2014, to bring together the diverse members essential for a successful approach to the prevention and treatment of PH. The participants included university researchers, clinical experts, and members of the Food and Drug Administration, the National Institutes of Health, and pharmaceutical companies. This unique collection of stakeholders in PH included more than 100 attendees. The goal of the DDDS-PH is to advance the field by providing a forum to develop a new collaborative vision to help evolve the approach to PH. The DDDS-PH will be held yearly, with meeting locations alternating between Europe and the United States.
The first DDDS-PH was a striking success. Eight new experimental therapies were discussed. These all arise from advances in basic science that have been adapted to the problem of PH, and they represent the cutting edge of vascular biology. The symposium summary and program, along with recordings of each session, can be found on the PVRI website, http://www.pvri.info/content/pvri-drug-discovery-and-development-symposium-summary#.VBHToWPG9yI.
Bone morphogenic protein receptor type 2 (BMPR2) insufficiency is the most common known mechanism leading to PAH, causing a majority of PAH by downregulation and about 15%–20% through heritable variants. The group at Stanford, represented by Marlene Rabinovitch, Edda Spiekerkoetter, and Roham Zamanian, showed early data testing tacrolimus in PH cells and patients, based on a high-throughput screening of molecules that would restore BMPR2 function in vitro. 1 This exciting approach is in its infancy but will undoubtedly expand and lead to future approaches. Paul Hassoun reviewed the data that inflammation and altered immunity have been increasingly recognized as important features of PH, with infiltration of inflammatory cells (e.g., macrophages and T and B lymphocytes), lymphoid neogenesis (e.g., formation of bronchus-associated lymphoid tissue structure [BALT]), and increased expression of inflammatory mediators and their receptors in remodeled pulmonary vessels. 2
Histone deacetylase (HDAC) inhibition was discussed by Martin Wilkins, who made a case for study in humans based on promising cell and animal data where HDAC inhibition prevented PH. 3 Application of microRNA approaches and epigenetic modification were presented by Sebastian Bonnet, showing that apolipoprotein A-I mimetic peptide 4F rescues PH by inducing microRNA-193-3p. 4
A second session focused on approaches to preserve and improve RV function in PH. Serpil Erzurum reviewed known neurohumoral and molecular associations with RV failure, 5 and Evangelos Michelakis gave a comprehensive review of the impaired mitochondrial processing of substrate and the downstream abnormalities that result and suggested mitochondrial rescue therapies. 6 Anton Vonk Noordegraaf reviewed data on beta adrenergic blockade and the rationale for further study on RV function in PH. 7 From the laboratory of Jane Leopold came the finding that gene rescue of sarcoplasmic reticulum Ca2+-ATPase 2 (SERCA2a) improves vascular reactivity and NO production and reduces proliferative changes in experimental PH. 8 These approaches are just some of the numerous potential treatments that need development and testing in order to discover whether they have efficacy in human PH.
The third session discussed approaches to clinical trials. Patricia Keegan, director of the Center for Drug Evaluation and Research, reviewed the evolution of clinical trial design in oncology toward the current approach of targeted drug testing of smaller numbers of patients using adaptive, concurrent, and enriched protocols. A promising new approach is the identification of cohorts with biological similarities that might respond to a drug targeted to the abnormality, similar to personalized medicine. Dr. Keegan exhorted the PH world to utilize approaches similar to those in oncologic research, taking risks with drugs showing good potential in selected cohorts of PH patients. The experience with imatinib in PH, which many think was a failure or inability to identify the biology of susceptible patients and therefore streamline the clinical trial, was reviewed by Ardi Ghofrani. With further experiments to identify the correct targets, the possibility that tyrosine kinase inhibition will have efficacy is still strong. Roham Zamanian discussed the preliminary data on use of tacrolimus in PAH patients, with an emphasis on biological measurements related to drug targets.
The next DDDS-PH is scheduled to be held in London, England, during the second week of June 2015. The goals are to connect European and American leaders in PH research to expand the dialogue about newer approaches to the worldwide problem of PH and to leverage the strengths of each group's expertise and interest, including academia, pharmaceutical companies, regulatory agencies, and medical and lay societies. Based on newer discoveries, the future of PH research and treatment is looking bright.