Innovative Drug Development Initiative Research Articles

Pulmonary hypertension in the setting of interstitial lung disease: Approach to managementand treatment. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative-Group 3 Pulmonary Hypertension.

Pulmonary hypertension (PH)due to interstitial lung disease (ILD),a commonly encountered complication of fibrotic ILDs, is associated with significant morbidity and mortality. Until recently, the studies of pulmonary vasodilator therapy in PH-ILDhave been largely disappointing, with some even demonstrating the potential for harm. This paper is part of a series of Consensus Statements from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative for Group 3 Pulmonary Hypertension, with prior publications covering pathogenesis, prevalence, clinical features, phenotyping, clinical trials, and impact of PH-ILD.It offers a comprehensive review of and a holistic approach to treatment of PH-ILD,including the management of underlying interstitial lung diseases, importance of treating the comorbidities, emphasis on importance of exercise and palliation of dyspnea, and review of the most up-to-date guidelines for referral for potential lung transplant work up. It also summarizes the prior, ongoing, and possibly future studies in treatment of the vascular derangement of this morbid condition.

Pathogenesis, clinical features, and phenotypes of pulmonary hypertension associated with interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative - Group 3 Pulmonary Hypertension.

Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes.

Pulmonary hypertension in interstitial lung disease: Clinical trial design and endpoints: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative-Group 3 Pulmonary Hypertension.

Pulmonary hypertension (PH) associated with interstitial lung disease (ILD) is an attractive target for clinical trials of PH medications. There are many factors that need to be considered to prime such studies for success. The patient phenotype most likely to respond to the intervention requires weighing the extent of the parenchymal lung disease against the severity of the hemodynamic impairment. The inclusion criteria should not be too restrictive, thus enabling recruitment. The trial should be of sufficient duration to meet the chosen endpoint which should reflect how the patient feels, functions, or survives. This paper summarizes prior studies in PH-ILD and provides a framework of the type of studies to be considered. Inclusion criteria, clinical trial endpoints, and pharmacovigilance in the context of PH-ILD trials are also addressed. Through lessons learnt from prior studies, suggestionsand guidance for future clinical trials in PH-ILD are also provided.

Clinical significance of pulmonary hypertension in interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's innovative drug development initiative-Group 3 pulmonary hypertension.

Pulmonary hypertension (PH) has been linked to worse outcomes in chronic lung diseases. The presence of PH in the setting of underlying Interstitial Lung Disease (ILD) is strongly associated with decreased exercise and functional capacity, an increased risk of hospitalizations and death. Examining the scope of this issue and its impact on patients is the first step in trying to define a roadmap to facilitate and encourage future research in this area. The aim of our working group is to strengthen the communities understanding of PH due to lung diseases and to improve the care and quality of life of affected patients. This introductory statement provides a broad overview and lays the foundation for further in‐depth papers on specific topics pertaining to PH‐ILD.

Repurposing of medications for pulmonary arterial hypertension.

This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute’s Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem.

Novel composite clinical endpoints and risk scores used in clinical trials in pulmonary arterial hypertension.

This manuscript on endpoints incorporates the broad experience of members of Pulmonary Vascular Research Institute’s Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It reviews our current understanding of endpoints used in phase 2 and 3 trials for pulmonary hypertension and discusses in detail the value of newer approaches. These include the roles of composite endpoints and how these can be developed and validated. The newer concept of risk analysis is also discussed, including how such risk scores might be utilised as endpoints in clinical trials.

Clinical trial design in phase 2 and 3 trials for pulmonary hypertension.

This article on clinical trial design incorporates the broad experience of members of the Pulmonary Vascular Research Institute’s (PVRI) Innovative Drug Development Initiative (IDDI) as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It is increasingly clear that the design of phase 2 and 3 trials in pulmonary hypertension will have to diversify from the traditional randomised double-blind design, given the anticipated need to trial novel therapeutic approaches in the immediate future. This article reviews a wide range of differing approaches and places these into context within the field of pulmonary hypertension.

The Innovative Drug Development Initiative (IDDI) of the Pulmonary Vascular Research Institute (PVRI)

The Innovative Drug Development Initiative (IDDI) of the Pulmonary Vascular Research Institute (PVRI)