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 industry-sponsored clinical research
on PARP1 inhibitor is currently entirely cancer-oriented. Nonetheless, AstraZeneca Canada
accepted to support an early phase clinical trial through in-kind contribution, but the
support from foundations and federal agencies is critical to catalyze early-stage development
of PARP1 inhibitors for other indications, especially for orphan diseases. A CIHR Project
Scheme grant will thus be submitted on September 15 2017, proposing a Phase 1, followed by a
Phase 2 trial that will be conducted in recognized PAH programs throughout Canada. At this
stage, however, we propose a pilot study to assess the feasibility of the proposed trials in
the PAH population. The overall HYPOTHESIS is that PARP1 inhibition with olaparib is a safe
and effective therapy for PAH.
The primary objective of the study is to confirm feasibility, to support the safety of using
olaparib in PAH patients, and precise the sample size of the coming Phase 1B trial. The
feasibility of the comprehensive patient phenotyping that will be proposed within the phase
1B trial will thus be assessed, in addition to adverse events and efficacy signals.
***OPTION pilot trial was merged with the new OPTION multicenter trial (NCT03782818)***