Inclusion Criteria:
1. Age ≥ 18 years. 2. Screening consistent with a diagnosis of precapillary PH (mPAP > 25 mmHg, PCWP < 18
mmHg, PVR >4WU) that is due to either:
1. WSPH Group 1 PH (i.e., PAH of any of the following subtypes)
- - Drug- or toxin-induced PAH.
- - PAH associated with connective tissue disease.
- - PAH associated with simple, congenital systemic-to-pulmonary shunts at least
1 year following shunt repair.
2. WSPH Group 3 PH as defined by one of the following:
- - CT within 6-months of screening that demonstrates diffuse parenchymal lung
disease.
- - FVC < 70% of predicted for this cohort only.
3. Symptomatic pulmonary hypertension classified as WHO functional class
Screening Period RHC (within 10 days prior to week 0 visit) documenting a minimum PVR
of ≥ 4 Wood units. 5. Pulmonary function tests within 6 months prior to Screening as follows:
1. Total lung capacity > 70% predicted; or if between 60% to 70% predicted, or not
possible to be determined (e.g., WSPH Group 3), confirmatory high- resolution
computed tomography (CT) indicating no more than mild interstitial lung disease
per investigator interpretation; or,
2. Forced expiratory volume (first second) (FEV1)/forced vital capacity (FVC) > 70%
predicted. 3. For subjects with a history of lobectomy or pneumonectomy, and for whom there are
no population-based normalization methods, assessment based on residual lung
volume will be permitted to assess eligibility.
6. Ventilation-perfusion (VQ) scan, a CT pulmonary angiogram (CTPA) or pulmonary
angiography, with findings that rule out chronic thromboembolic pulmonary
hypertension. Can be performed any time prior to Screening or conducted during the
Screening Period.
7. 6MWD ≥ 100 and ≤ 550 meters repeated twice during Screening Period and both values
within 15% of each other, calculated from the highest value.
8. On a standard of care PAH therapy at stable (per SOC) dose levels for at least 30 days
prior to screening.
9. Females of childbearing potential must satisfy following (details outlined in
appendix, under Contraceptive Guidance and Collection of Pregnancy Information):
1. Have 2 negative pregnancy tests as verified by the investigator prior to starting
study and must agree to ongoing pregnancy testing during the study and at end of
study treatment.
2. If sexually active, must have used, and agree to continue to use, highly
effective contraception without interruption, for at least 30 days prior to
starting investigational product (IP), during the study (including dose
interruptions), and for 90 days after discontinuation of study treatment.
3. Refrain from breastfeeding a child or donating blood, eggs, or ovum for the
duration of the study and for at least 90 days after the last dose of study
treatment.
10. Male participants must:
1. Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made
from natural (animal) membrane (for example, polyurethane), during sexual contact
with a pregnant female or a female of childbearing potential while participating
in the study, during dose interruptions, and for at least 90 days following IP
discontinuation, even if he has undergone a successful vasectomy.
2. Refrain from donating sperm for the duration of the study and for 90 days after
the last dose of study treatment.
11. Ability to adhere to the study visit schedule and understand and comply with all
protocol requirements.
12. Ability to understand and provide written informed consent.
Exclusion Criteria:
1. Started or stopped receiving any general supportive therapy for pulmonary hypertension
within 30 days prior to Week 0 Visit. 2. Received IV inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within
30 days prior to Week 0 Visit. 3. History of atrial septostomy within 180 days prior to Screening Visit. 4. History of more than moderate obstructive sleep apnea that is untreated. 5. Prior exposure to oral sirolimus or any other mTOR inhibitor within last three months. 6. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days
prior to Week 0 Visit or planned initiation during the study (participants who are
stable in the maintenance phase of a program and who will continue for the duration of
the study are eligible)
7. Uncontrolled systemic hypertension as evidenced by sitting systolic BP > 160 mmHg or
sitting diastolic BP > 100 mmHg during Screening Visit after a period of rest. 8. Systolic BP < 90 mmHg during Screening Visit or at baseline. 9. History of known pericardial constriction. 10. RHC contraindicated during the study per investigator. 11. Personal or family history of long QTc syndrome or sudden cardiac death. 12. Cerebrovascular accident within 3 months of Week 0 Visit. 13. History of restrictive or constrictive cardiomyopathy. 14. Left ventricular ejection fraction < 45% on echocardiogram performed within 6 months
prior to Screening Period (or done as a part of the Screening Period), or PCWP > 18
mmHg as determined in the Screening Period RHC. 15. Any current symptomatic coronary disease (myocardial infarction, percutaneous coronary
intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain in
the past 6 months prior to Screening Visit)
16. Acutely decompensated left or right heart failure within 30 days prior to Week 0
Visit, as per investigator assessment. 17. Known diagnosis (as determined by echocardiography) of significant (≥ 2+
regurgitation) mitral regurgitation or aortic regurgitation valvular disease. 18. Any of the following clinical laboratory values during the Screening Period prior to. Week 0 Visit:
1. Baseline Hgb > 16.0 g/dL within 28 days of Week 0 Visit. 2. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >
3x upper limit of normal (ULN) or total bilirubin > 1.5 x ULN within 28 days of
Week 0 Visit. 3. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (4-variable Modification
of Diet in Renal Disease equation) within 28 days of Week 0 Visit or required
renal replacement therapy within 90 days. 19. History of opportunistic infection (e.g., invasive candidiasis or Pneumocystis
pneumonia) within 6 months prior to Screening; serious local infection (e.g.,
cellulitis, abscess) or systemic infection (e.g., septicemia) within 3 months prior to
Screening. 20. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant
proteins or lactose excipients in IP. 21. Major surgery within 8 weeks prior to Week 0 Visit. Participants must have completely
recovered from any previous surgery prior to Week 0 Visit. 22. Prior heart or heart-lung transplants. 23. Life expectancy of < 12 months (per PI determination)
24. Pregnant or breastfeeding females. 25. At any time in the 30 days prior to the Screening Period received > 20 mg/day of
prednisone (or equivalent) or started or changed the dose of a systemic
corticosteroid.
Participants receiving stable doses of ≤ 20 mg prednisone (or equivalent) in 30 days
prior to the Screening Period are permitted in the study.
26. History of active malignancy within the past 5-years, with the exception of fully
excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous
cell carcinomas of the skin. 27. History of clinically significant (as determined by the investigator) non-PAH related
cardiac, endocrine, hematologic, hepatic, immune, metabolic, urologic, pulmonary,
neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or other disease that
may limit participation in the study. 28. Participation in another clinical trial involving intervention with another
investigational drug or approved therapy for investigational use within 4 weeks prior
to Week 0 Visit, or if the half-life of the previous product is known, within 5x the
half-life prior to Week 0 Visit, whichever is longer. 29. Participation in another clinical trial involving an investigational device within 4
weeks prior to Week 0 Visit. 30. Unwillingness or inability to comply with the protocol- required procedures
