Angiogenic Imaging in Pulmonary Arterial Hypertension

PAH is a disease of progressive remodeling and obliteration of the distal pulmonary
vasculature. The overexpression of VEGF-A in the pulmonary vasculature of patients with PAH
and animal models of disease is thought to reflect a process of disordered angiogenesis that
is tightly coupled to disease progression. It is hypothesized that positron emission
tomography (PET)-CT scan utilizing [89Zr]-bevacizumab, a radioisotope-conjugated humanized
monoclonal antibody against VEGF-A, would provide a sensitive and specific molecular imaging
modality to detect pulmonary vascular remodeling activity.

To test this hypothesis the investigators propose a Phase I/II pilot study to enroll 10
patients with known severe idiopathic or familial PAH, 10 individuals with
exercise-associated PAH (EPAH), thought to be a mild and early stage of PAH, and 10 healthy
volunteers with no evidence of cardiopulmonary disease. This pilot study will compare
standardized uptake values (SUV) for the retention of [89Zr]-bevacizumab in the distal
pulmonary vasculature in these three populations. The kinetics of equilibration and wash-out
of this probe will be assessed with sequential scans at 4 and 7 days following the injection
of radionuclide. In patients with PAH or EPAH, repeat scans will be performed 1 year after
the initial scan to assess whether changes in clinical status correlate with
[89Zr]-bevacizumab retention.

The ability of these protocols to discriminate between the lungs of healthy individuals
versus patients with PAH or EPAH will be evaluated using the measure of peripheral lung
tissue probe SUV, corresponding to distal pulmonary vessel uptake, normalized to the proximal
aortic SUV, corresponding to the blood pool. These data will be used to define normative
values for healthy controls versus PAH patients, and to generate cutoffs in signaling ratios
with optimal sensitivity and specificity for disease detection. These normative ranges will
be applied to the EPAH cohort to determine if this test retains sensitivity and specificity
for a potentially milder, earlier form of PAH.

This study is divided into 4 Aims:

AIM 1: Test the hypothesis that expression of VEGF-A discerned by [89Zr]-bevacizumab imaging
is increased in the distal pulmonary vascular bed in PAH patients compared to healthy
individuals.

AIM 2: Test the hypothesis that expression of VEGF-A discerned by [89Zr]-bevacizumab imaging
is increased in the distal pulmonary vascular bed in patients with exercise-associated PAH
compared to healthy individuals.

AIM 3: Ascertain whether or not distal pulmonary vascular uptake of [89Zr]-bevacizumab
correlates with clinical markers of PAH severity, including 6 minute walk distance, New York
Heart Association functional class, right atrial pressure, mean pulmonary artery pressure,
pulmonary vascular resistance, cardiac index, NT-proBNP, tricuspid annular plane systolic
excursion (TAPSE) by echocardiography.

AIM 4: Ascertain whether or not changes in distal pulmonary vascular uptake of
[89Zr]-bevacizumab over 1 year in patients with PAH or EPAH correlates with changes in
clinical status based on clinical markers of PAH severity.

Inclusion Criteria:

- Age ≥18 years at screening;

- Documented diagnosis Group 1 PAH confirmed by resting mean pulmonary artery pressure
greater than 25 mm of Hg, pulmonary vascular resistance greater than 3 Wood units, and
pulmonary wedge pressure less than 12 mm of Hg measured by right heart catheterization
at the time of diagnosis and before initiation of PAH specific therapy clinically
stable for 60 or more days prior to enrollment, defined as no changes in medical
regimen and no hospitalizations;

- Prior diagnosis of exercise-associated PAH (EPAH) confirmed by normal resting
hemodynamics (mean pulmonary artery pressure < 25 mm of Hg, pulmonary artery wedge
pressure < 12 mm of Hg, and pulmonary vascular resistance < 3 Wood units) measured by
right heart catheterization at rest and abnormal hemodynamic response to exercise
characterized by increase in mean pulmonary artery pressure > 30 mm Hg, pulmonary
artery wedge pressure < 20 mm Hg, and pulmonary vascular resistance > 1 Wood unit at
peak exercise and cardiac output less than 10 L/min before initiation of any PAH
specific therapy. Patients need to be clinically stable for 60 or more days prior to
enrollment, defined as no changes in medical regimen and no hospitalizations;

- Willingness to participate as evidenced by signing of the informed consent;

Exclusion Criteria:

- Prior history of chronic infectious disease, tuberculosis, or severe fungal disease;
chronic hepatitis B or C infection; renal insufficiency; interstitial pneumonitis,
bronchiectasis, or pulmonary fibrosis; known chronic pericardial effusion, pleural
effusion, or ascites; chronic liver disease; myeloproliferative disorders in the past
5 years; non-basal cell malignancy or treated lymphoproliferative disease within the
past 5 years; known HIV positive; life expectancy of <3 years;

- Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative
colitis or Crohn's disease;

- White blood cell count <2,500/uL, hematocrit < 30 percent, or platelet count <
50,000/uL;

- Elevated liver transaminase levels (AST or ALT) 20 % above upper limit of normal (ULN)
or albumin 20 % below the lower limit of normal (LLN);

- Creatinine clearance < 45 mL/min as estimated with the Cockroft-Gault equation;

- Women who are pregnant or breastfeeding;

- Men or women who plan to have children during the study period or who are unwilling to
use effective forms of contraception;

- Known active cancer;

- Chronic use of oral steroid therapy or other immunosuppressive or biologic response
modifiers (see Exclusionary Medication List in Manual of Operations). Eligible study
participants will be encouraged to have up to date pneumococcal and influenza
vaccinations as recommended based on their age and underlying medical conditions;

- Evidence of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis in the
past 12 months by chest X-ray. For participants who have not had a chest X-ray during
the 12 months prior to enrollment in the study, a chest X-ray will be obtained at
baseline as part of the study protocol;

- New York Heart Association Class IV congestive heart failure;

- Severe asthma or COPD defined by FEV1 less than 50% predicted and FEV1/FVC less than
70% per PFTs in the past 12 months;

- Active tobacco use during the prior 10 years;