Throughout the past twenty years, numerous specific pharmacologic agents targeting the
endothelial dysfunction associated with PAH have emerged. Short term placebo-controlled
randomized trials assessing PAH-specific monotherapy with these molecules have reported
improvements in pulmonary hemodynamics and exercise capacity. A recent meta-analysis also
documented a reduction in short-term mortality of about ≈40% with such therapies. Several
randomized clinical trials evaluating PAH-specific combination therapy have been conducted.
Our recent meta-analysis showed that combination therapy was associated with a 35% risk
reduction for the occurrence of clinical worsening compared to monotherapy. Nonetheless, the
investigators also showed 17% of PAH patients receiving combination therapy still experienced
clinical worsening over a median exposure of 16 weeks. Moreover, long-term survival on
PAH-specific also therapy remains poor in the modern era, with a yearly mortality rate of 15
% in incident idiopathic PAH. The identification of innovative therapeutic targets and
validation of these complementary therapeutic interventions are thus urgently needed in PAH.
The investigators and others (K. Stenmark, University of Colorado and H. Bogaard, VU
University Medical Center, Amsterdam, personal communications), have published strong
evidence that BRD4 plays a key role in the pathological phenotype in PAH accounting for
disease progression and showed that BRD4 inhibition can reverse PAH in several animal models.
Intriguingly, coronary artery disease (CAD) and metabolic syndrome are more prevalent in PAH
compared with the global population, suggesting a link between these diseases. Interestingly,
BRD4 is also a trigger for calcification and remodeling processes and regulates transcription
of lipoprotein and inflammatory factors, all of which are important in PAH and CAD.
Apabetalone, an orally available BRD4 inhibitor, is now in a clinical development stage with
a good safety profile.
The overall objective of the study is to explore the efficacy and safety of apabetalone as an
add-on therapy for adult PAH patients and to inform the conduct and the design of a Phase 3
trial.
The primary objective of the study is to assess the efficacy of apabetalone as evaluated by
the change in PVR over a period of 24 weeks compared to placebo in adult subjects with PAH on
stable background therapy.
Secondary objectives include changes at week 24 in 6MWD, plasma NT-proBNP concentration, WHO
functional class, ESC/ERS risk stratification score, health-related quality of life and
additional hemodynamic data from right heart.
Exploratory objectives are to evaluate the effects of apabetalone compared to placebo in
adult subjects with PAH on mortality and clinically relevant morbidity events, and on
circulating levels and transcription changes in whole blood markers of metabolism, vascular
calcification, inflammation, DNA damage and leucocyte expression of BMPR2.
Phase:
Phase 2
Details
Lead Sponsor:
Institut universitaire de cardiologie et de pneumologie de Québec, University Laval
Collaborators:
Canadian Institutes of Health Research (CIHR) Resverlogix Corp