This is an adaptive, 2-part, randomized, multicenter, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of IKT-001 in adult participants with WHO Group 1 PAH.

Inclusion Criteria:

• Documented diagnosis of WHO PAH Group 1 in any of the following subtypes:

  • Idiopathic PAH
  • Heritable PAH
  • Drug/toxin-induced PAH
  • PAH associated with connective tissue disease (CTD)
  • PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair

• Men and women 18 and 75 years of age (inclusive)

• Must have a body mass index (BMI) of ≥18.5 kg/m^2 and ≤35.0 kg/m^2 at screening.

• Baseline RHC performed during the Screening Period documenting a PVR of ≥ 400 dyn/sec/cm^5 ; pulmonary capillary wedge pressure (PCWP) ≤15 mmHg and mean pulmonary artery pressure (mPAP) >20 mmHg. PVR enrichment criteria to ensure population baseline PVR >700 dynes/sec/cm^5

• On stable doses of background PAH therapy including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, prostacyclins, and soluble guanylate cyclase stimulators for ≥90 days prior to screening. Current use of sotatercept is not permitted.

• 6MWD ≥ 100 and ≤ 475 m

Exclusion Criteria:

• Diagnosis of PAH WHO Groups 2, 3, 4, or 5.

• Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH, PAH associated with portal hypertension, schistosomiasis-associated PAH, and pulmonary veno-occlusive disease.

• Any of the following blood pressure-related values or abnormalities: Uncontrolled systemic hypertension as evidenced by sitting systolic BP >160 mmHg or sitting diastolic BP >100 mmHg at screening, Baseline systolic BP <90 mmHg at screening, Syncope within 3 months prior to screening

• History of restrictive, constrictive, or congestive cardiomyopathy.

• ECG with Fridericia's corrected QT interval (QTcF) ≥ 450 msec in males or ≥ 470 msec in females at screening or ≥500 msec in the presence of a right bundle branch block.

• Personal or family history of long QT syndrome or sudden cardiac death.

• Presence of a CardioMEMS device or any other implanted hemodynamic monitoring device.

• Forced vital capacity (FVC) <70 percent on pulmonary function test (PFT) performed no more than 6 months prior to screening; or if FVC is 60 percent to 69 percent, must have a chest computed tomography scan within 12 months with no more than mild interstitial lung disease.

• History of atrial fibrillation or atrial flutter.

• History of cerebrovascular accident, intracranial hemorrhage, or subdural hematoma at anytime, or a fall associated with head trauma within 3 months of screening.

• Acutely decompensated right heart failure within 30 days prior to screening, as per investigator assessment.

• Clinically significant ischemic, valvular, constrictive heart disease, or heart failure with preserved ejection fraction in the opinion of the investigator.

• History of pneumonectomy.

• Untreated or inadequately treated (in the opinion of the investigator) obstructive sleep apnea.

• Acute or chronic hepatitis B or C infection, defined as:

  • Hepatitis B virus: a positive hepatitis B surface antigen test or a positive hepatitis B core antibody test with detectable DNA
  • Hepatitis C virus (HCV): a positive hepatitis C antibody test with detectable HCV ribonucleic acid (RNA).Participants with a positive hepatitis C antibody test, but no detectable HCV RNA who completed treatment with direct-acting antivirals may be considered after discussion with the medical monitor.

• History of or currently diagnosed with a bleeding disorder, including but not limited to hemophilia, von Willebrand disease, thrombocytopenia, or significant bleeding history defined as any bleeding event requiring medical intervention.

• Received treatment with any of the following excluded medications:

  • Currently receiving strong cytochrome P450 (CYP) 3A inducers or CYP3A inhibitors (except for topical administration)
  • Currently receiving or anticipated need to receive any anticoagulant (e.g., heparins, vitamin K antagonists, direct oral anticoagulants, or direct thrombin inhibitors).
  • Current use of sotatercept. Note: participants who previously received sotatercept may be considered if the last dose administered was >6 months prior to screening, participant had no significant bleeding events while on sotatercept.

• Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to screening 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).

• History of atrial septostomy within 180 days prior to screening.

• Current participation in another investigational clinical trial and/or receipt of any investigational medication within 90 days prior to screening.

• Previous randomization into this or another IKT-001 study.

• Any social, behavioral, or medical reason that would preclude completion of the study, in the judgement of the investigator.

• Currently lactating, pregnant or planning on becoming pregnant during the study.

• Prior receipt of a solid organ transplant or stem cell transplant.

• Planned surgery that would require any study drug interruption or interfere with study assessments during the study (minor procedures may be allowed in consultation with the medical monitor).

• Malignancy within the last 5 years prior to consent except completely treated non-metastatic-basal cell, squamous cell, in situ cervical cancer, and clinically localized National Comprehensive Cancer Network very low to low risk prostate cancer under active surveillance.