The main OBJECTIVE of this proposal is to extend our preclinical findings on the role of DNA
damage and poly(ADP-ribose) polymerases (PARP) inhibition as a therapy for a devastating
disease, pulmonary arterial hypertension (PAH), to early-phase clinical trials. We, and
others, have published strong evidence that DNA damage accounts for disease progression in
PAH and showed that PARP1 inhibition can reverse PAH in several animal models1.
Interestingly, PARP1 inhibition is also cardioprotective. Olaparib, an orally available PARP1
inhibitor, can reverse cancer growth in animals and humans with a good safety profile, and is
now approved for the treatment of ovarian cancer in Canada, Europe and the USA. The time is
thus right to translate our findings in human PAH.
The primary objective of this Phase 1B study is to confirm the safety of using olaparib in
PAH patients, and precise the sample size of a future Phase 2 trial. In addition to safety,
efficacy signals will thus be assessed.
Overall, 20 well-characterized PAH patients that have been stable for >4 months on standard
PAH-therapies, as per guidelines will be recruited. The initial Health Canada approval will
be obtained. Olaparib will be provided by AstraZeneca Canada, but AZ had no input into the
trial design and will not be involved in the conduct of the trial, analysis, interpretation
of the results or the final manuscript.
A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of PAH
Given that PAH is a chronic disease and that patients may be at higher risk for drug-related
adverse events (e.g. anemia), olaparib will be started at low-dose (100mg BID), then
up-titrated weekly by 100mg BID up to 200mg BID (n=5, group 1) or 300mg BID (n=15, group 2)
for a total treatment duration (including the up-titration phase) of 24 weeks. Using 100mg
and 150mg tablets will allow minimizing the number of tablets taken (e.g. 2 x 150mg tablets
BID) or adjusting the dose in case of drug-related adverse events (e.g. 250mg BID using 100mg
and 150mg tablets).
Patients will be regularly followed to assess whether side effects are observed and whether
olaparib can be up-titrated.
At baseline and week 24, a cardiac catheterization will assess changes in pulmonary
hemodynamics and RV function.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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