BACKGROUND PAH is a progressive and multifactorial condition characterized by the chronic elevation of pulmonary artery (PA) pressure leading to RV failure. In spite of currently approved therapies, patients with PAH have poor quality of life and the 3-year survival of idiopathic PAH remains \~55%. The identification and characterization of new therapeutic targets is thus an urgent need.
In recent years, it has become increasingly appreciated that, as in cancer cells, PAH-PA smooth muscle cells (PASMCs) are exposed to stressful conditions, jeopardizing their survival. To deal with these insults, these cells have developed complementary pathways, allowing them to survive and proliferate and leading to intense remodelling of distal PA. Central to these strategies are the activation of the DNA repair machinery. Survival of these cells is associated with an over-efficient activation of PAPR1, a predominant mechanism involved in DNA repair, and pharmacological inhibition of PARP1 reverses PAH in human cells and clinically relevant animal models.
Recently, Olaparib, an orally available PARP1 inhibitor, was shown to be safe, well tolerated and effective in treating cancers and was approved for the treatment of ovarian cancer.
OLAPARIB IN PAH: A PILOT STUDY The study population will include 6 well-characterized PAH patients that have been stable for \>4 months on standard PAH-therapies, as per guidelines.
The primary objective of the study is to confirm the feasibility for a future early stage clinical trial and provide early evidence that Olaparib may be effective in PAH.
Exploratory efficacy end-point: The exploratory efficacy endpoint will be the change in pulmonary vascular resistance (PVR) at week 16. Other exploratory efficacy end-points will include changes in: 1) additional haemodynamic data by catheterization; 2) 6-min walk distance (6MWD); 3) RV volumes and mass (cardiac MRI) in eligible patients; 4) WHO functional class; 5) NT-proBNP levels; 6) Quality of life assessed using the CAMPHOR questionnaire.
Study design: This is a standard-design, dose-escalating pilot study. In line with most pilot and safety studies, the design is open-label. A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of medication. Patients will be given progressive doses of olaparib up to 400mg BID for 16 weeks. Patients will be regularly followed. At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function.
Toxicity monitoring/withdrawal: Based on experience to date with olaparib, doses up to 400mg BID should be tolerated. Subjects may experience mild side effects or other events that the investigator may consider related to study drug but not of sufficient clinical significance to warrant withdrawal from treatment. At the investigators' discretion, olaparib may be managed by dose reduction. If the lower dose is not tolerated, the patient will be withdrawn from the study. Subjects who require a dose reduction should be maintained at the reduced dose level through to the end of the 16-week treatment period. Adverse events will be submitted to our ethics committees.
Analysis: This pilot study is not meant to prove efficacy. As a result, power calculations were not determined. The safety and exploratory endpoint analysis will be only descriptive. Nonetheless, it is hoped that olaparib will be associated with hemodynamic improvements, giving precision about the dose to be tested and sample size calculation for subsequent studies. Thus, there is a need for assessment of the exploratory efficacy endpoints. These analyses will be based on the per protocol set (all treated patients who did not violate the protocol in a way that might influence the evaluation of the effect of the study drug on the primary endpoint).
