The main OBJECTIVE of this proposal is to extend the investigator's preclinical findings on the role of epigenetics and DNA damage and Bromodomain-Containing Protein 4 (BRD4) inhibition as a therapy for a devastating disease, pulmonary arterial hypertension (PAH).

There is strong evidence that BRD4 plays a key role in the pathological phenotype in PAH accounting for disease progression and 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.

At this stage, the investigators propose a pilot study to assess the feasibility of a Phase 2 clinical trial assessing apabetalone in the PAH population. The overall HYPOTHESIS is that BRD4 inhibition with apabetalone is a safe and effective therapy for PAH.

In line with most pilot and safety studies, this is a two-centre (Quebec and Calgary) open-label trial. A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of medication. Patients will be given doses of apabetalone 100mg 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.

Inclusion Criteria:

1. Adults (18-75 yrs) with PAH of idiopathic or hereditary origin, associated with connective tissue diseases, or anorexigen use.

2. Mean PA pressure ≥25mmHg, with pulmonary artery wedge pressure ≤15mmHg. In addition, subjects will be required meet the following hemodynamic criteria:

   1. PVR >480 dyn.s.cm-5
   2. Negative vasoreactivity test mandatory in idiopathic, heritable, and drug/toxin induced PAH (at baseline or during previous RHC).

3. World Health Organization functional class (WHO FC) II or III.

4. Appropriate stable therapy for PAH for ≥4 months before screening, including endothelin receptor antagonists (ERAs) other than bosentan and/or phosphodiesterase type 5 (PDE-5) inhibitors and/or prostanoids.

5. Two 6-min walk tests of 150-550m inclusive and within ±15% of each other (the latter being used as baseline value).

6. Patients must be able to understand the study procedures and agree to participate in the study by providing written informed consent.

7. Patients of childbearing potential must have a negative serum pregnancy test (β-hCG) within 72 hours prior to receiving the first dose of study treatment.

8. Patients must be postmenopausal, free from menses for >1 year, surgically sterilized, willing to use adequate contraception to prevent pregnancy, or agree to abstain from activities that could result in pregnancy, from enrollment through 3 months after the last dose of study treatment.

Exclusion Criteria:

1. PAH related to HIV infection, portal hypertension or congenital heart disease.

2. Pulmonary hypertension due to left heart disease (WHO PH group 2), lung disease and/or hypoxia (WHO PH group 3), chronic thromboembolic pulmonary hypertension (WHO PH group 4), or unclear multifactorial mechanisms (WHO PH group 5).

3. Known or suspected pulmonary veno-occlusive disease (PVOD).

4. Severe restrictive lung disease (Total Lung Capacity <60% predicted)

5. Severe obstructive lung disease (FEV1/FVC < 60% after a bronchodilator)

6. DLCO <40%

7. Systolic blood pressure <90 mmHg

8. Resting heart rate in the awake patient <50 BPM or >110 BPM

9. Clinically unstable right heart failure within the last 3 months or are WHO FC IV.

10. Received any investigational drug within 30 days of screening.

11. Body mass index (BMI) <18 or >40 kg/m2 at screening.

12. Patients must not be pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and for 3 months after the last dose of study treatment.

13. Cardiopulmonary rehabilitation program based on exercise (planned or started ≤12 weeks prior to Day 1).

14. Presence of ≥3 of the following risk factors for heart failure with preserved ejection fraction at screening:

    1. BMI >30 kg/m2.
    2. Diabetes mellitus of any type.
    3. Essential hypertension.
    4. Coronary artery disease, i.e., any of the following:

    i. History of stable angina ii. More than 50% stenosis in a coronary artery (by coronary angiography) iii. History of myocardial infarction iv. History of or planned coronary artery bypass grafting and/or coronary artery stenting.

15. A ventilation-perfusion lung scan or pulmonary angiography indicative of thromboembolic disease.

16. Evidence of organ dysfunction other than right heart failure, including:

    1. Creatinine clearance <45 ml/min (using the Cockroft-Gault formula).
    2. Serum AST or ALT >3 x ULN.
    3. Total bilirubin > 1.5 x ULN.
    4. Childs-Pugh class B-C liver cirrhosis.
    5. Hemoglobin <100 g/L.
    6. Absolute neutrophil count < 1,500/μL .
    7. Platelets < 150,000/μL .

17. Anticipated survival less than 1 year due to concomitant disease.

18. History of cancer in the past 5 years (except for low grade and fully resolved non-melanoma skin cancer).

19. Hypersensitivity to the components of apabetalone or any excipient of their formulations.

Forbidden concomitant therapy:

• Any investigational drug other than the study treatment.
• Based on in vitro data and clinical exposure data, apabetalone is considered unlikely to cause clinically significant drug interactions through inhibition or induction of cytochrome P450 enzyme activity. Nonetheless, as the contribution of metabolic clearance to total drug clearance in man is unknown, potent inhibitors (ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfanavir) or inducers (Phenytoin, rifampicin, carbamazepine and phenobarbitone, nevirapine, modafinil and St John's Wort) of CYP3A4 must not be used during this study for any patient receiving apabetalone to ensure patient safety. Moreover, bosentan has been associated with a 5-10% risk or reversible raised in LFTs. Although there is no evidence of increased risk of apabetalone-related increases in LFTs amongst bosentan users, the use of bosentan will be forbidden during this study.