Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial

François Harel,Vincent Finnerty,Asmaa Mansour,Xavier Levac,Myriam Letourneau,Quang T Nguyen,Jocelyn Dupuis,Steve Provencher,Jean Guimond,Gad Abikhzer,David Langleben,Marie-Claude Guertin,Alain Fournier

doi:10.1007/s00259-017-3655-y

Abstract

PurposeThe adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study.MethodsThirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month.ResultsPulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution.ConclusionsIn this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed.Clinical trialClinicalTrials.gov, NCT02216279

Highlights

Pulmonary hypertension (PH) results from a progressive loss of lung perfusion
The lungs are a major site for circulating AM clearance [4] and pulmonary clearance of AM is reduced in animal models of pulmonary arterial hypertension (PAH) with reduced AM receptor expression [5,6,7]
The primary efficacy objective was to determine the capacity of PulmoBind lungs scan for detecting abnormal pulmonary circulation associated with PH

Summary

Introduction

Pulmonary hypertension (PH) results from a progressive loss of lung perfusion. Invasive measurement of pulmonary pressure by right heart catheterization is required for precise diagnosis and classification of PH. The lungs are a major site for circulating AM clearance [4] and pulmonary clearance of AM is reduced in animal models of pulmonary arterial hypertension (PAH) with reduced AM receptor expression [5,6,7]. Based on these premises, we developed AM derivatives that can be labeled with 99mTc for molecular SPECT imaging of the pulmonary circulation [7]. In the current phase II study, we aimed to determine the safety and establish the proof of principle for the use of PulmoBind in the diagnosis of human pulmonary vascular disease

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