New Trial Designs and Potential Therapies for Pulmonary Artery Hypertension

A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH. A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances over the past 2 decades in treatment of this disorder. However, these treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Because PAH is considered an orphan disease that is uniformly progressive and fatal, prior clinical trials evaluating novel therapies were relatively short in duration and were comprised of small populations of affected patients. These studies provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Accordingly, clinical development of novel therapies for PAH in the future will require trials of larger and perhaps more diverse patient cohorts who are studied for longer periods and with more robust and meaningful efficacy endpoints. The challenges posed by these requirements are substantial, and include From th

Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium

, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety in which proarrhythmic risk would be primarily assessed using nonclinical in vitro human models based on solid mechanistic considerations of torsades de pointes proarrhythmia. This new paradigm would shift the emphasis from the present approach that strongly relies on QTc prolongation (a surrogate marker of proarrhythmia) and could obviate the clinical Thorough QT study during later drug development. These discussions represent current thinking and suggestions for furthering our knowledge and understanding of the public health case for adopting a new, integrated nonclinical in vitro/in silico paradigm, the Comprehensive In Vitro Proarrhythmia Assay, for the assessment of a candidate drug's proarrhythmic liability, and for developing a public-private collaborative program to characterize the data content, quality, and approaches required to assess proarrhythmic risk in the absence of a Thorough QT study. This paper seeks to encourage multistakeholder input regarding this initiative and does not represent regulatory guidance. (Am Heart J 2014;0:1-9.) A Think Tank sponsored by Cardiac Safety Research Consortium (CSRC), Health and Environmental Sciences Institute (HESI), and Food and Drug Administration (FDA) was convened at FDA Headquarters on July 23, 2013, to discuss a potential new approach to assessing druginduced proarrhythmic risk. The current safety testing paradigm is based primarily on the predictive link between drug-induced in vitro hERG channel blockade and in vivo/clinical QT interval prolongation and torsades de pointes (TdP). Prolongation of the QT interval has been considered as an initiating factor in clinical TdP. Although the current paradigm has largely eliminated new drugs entering the market with unanticipated potential for torsade, it has important limitations and may have led to stopping the development of potentially valuable therapeutics. Therefore, a Comprehensive In vitro Proarrhythmia Assay (CiPA) was proposed as a new paradigm. It should be emphasized that the Think Tank was not designed to seek consensus endorsement of a fully defined and vetted new approach ready for immediate implementation. Rather, its goals were to suggest components of such a paradigm, identify weaknesses and areas for refinement, facilitate transparent stakeholder input and discussions, propose potential member organizations of a collaborative group to develop the specifics that would be needed, and consider the first pragmatic steps. These goals were accomplished, and such next steps are underway. Based on the principles of the US FDA Critical Path Initiative, the CSRC 1 was created to facilitate collaborations among academicians, industry professionals, and regulators to develop consensus approaches addressing cardiac and vascular safety issues that can arise in the development of new medical products. Executive summary The present cardiac safety paradigm (ICH S7B nonclinical guidance Although the present paradigm has largely eliminated the unanticipated discovery of new torsadogenic drugs entering the market, important limitations of the present approach include that block of I Kr alone is often insufficient in predicting delayed repolarization (itself a surrogate marker of proarrhythmia); increases in the QTc interval are highly sensitive but not very specific for predicting ventricular proarrhythmia risk; and there are clinically important drugs that block I Kr at therapeutic plasma concentrations that are not proarrhythmic. The bulk of the presentations and discussions, therefore, revolved around the following proposition: A new cardiac safety paradigm utilizing a novel array of nonclinical proarrhythmia assessments, combined with in silico predictive modelling of cellular electrophysiological effects, could make drug discovery and development efforts more efficient, move the major clinical/regulatory analysis concerning arrhythmogenic potential earlier in the drug discovery and development continuum, enhance the accuracy with which existing and/or new drugs are labelled relative to actual proarrhythmic risks, and increase the output of new chemical entities that benefit patients. The proposed paradigm, labeled the "Comprehensive In vitro Proarrhythmia Assay" (CiPA), is based on an established mechanistic understanding of TdP. To assess overall proarrhythmic risk, CiPA relies upon (a) characterization of electrophysiological effects of evolving or existing drugs on multiple human cardiac currents measured in heterologous expression systems, whose electrophysiological effects will then be integrated in silico by computer models reconstructing human cellular ventricular electrophysiology, and (b) confirmation of the electrophysiological effects in a myocyte assay such as human induced pluripotent stem cell-derived cardiomyocytes. Evaluations of hemodynamic and electrocardiographic (ECG) effects from standard nonclinical cardiovascular in vivo studies (as described in ICH S7A and S7B) will remain part of the new paradigm, along with careful ECG assessment in phase 1 studies to evaluate a drug's effects on ECG intervals (QTc, PR, and QRS durations), atrioventricular conduction, and heart rate. These later studies would confirm that there were no unanticipated clinical ECG changes as compared with the nonclinical testing; if unanticipated changes are found, the reasons for the discrepancy would need to be understood. With this new paradigm in place, the ICH S7B guideline 4 defining hERG as the primary ion channel of focus for proarrhythmia would need to be revised, and the Thorough QT (TQT) study described in ICH E14 guideline

Assessment of drug-induced increases in blood pressure during drug development: Report from the Cardiac Safety Research Consortium

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of blood pressure (BP) responses to drugs being developed for indications not of a direct cardiovascular (CV) nature. A wide range of drugs are associated with off-target BP increases, and both scientific attention and regulatory attention to this topic are increasing. The article provides a detailed summary of scientific discussions at a Cardiac Safety Research Consortium-sponsored Think Tank held on July 18, 2012, with the intention of moving toward consensus on how to most informatively collect and analyze BP data throughout clinical drug development to prospectively identify unacceptable CV risk and evaluate the benefit-risk relationship. The overall focus in on non-CV drugs, although many of the points also pertain to CV drugs. Brief consideration of how clinical assessment can be informed by nonclinical investigation is also outlined. These discussions present current thinking and suggestions for furthering our knowledge and understanding of off-target drug-induced BP increases and do not represent regulatory guidance. (Am Heart J 2013;165:477-88.

Blood pressure as an example of a biomarker that functions as a surrogate

There are many important uses of biomarkers in drug development. An area of particular interest is the use of biomarkers as surrogate end points. Only a small minority of biomarkers are established surrogate end points. Blood pressure is an example of a surrogate end point accepted by both clinicians and regulators. It was a plausible surrogate because of the large epidemiologic databases demonstrating a correlation between elevated blood pressures and adverse cardiovascular outcomes. That plausibility has been supported, however, by the numerous placebo-controlled outcome studies evaluating several pharmacologically distinct agents that showed an effect on stroke and coronary heart disease outcomes from lowering blood pressure