The main objective of the study is to assess the effect of treprostinil palmitil inhalation powder (TPIP) compared with placebo on pulmonary vascular resistance.

Inclusion Criteria:

• Participants must be ≥ 18 to ≤ 75 years at the time of signing the informed consent form (ICF).

• Participants must have a diagnosis of World Health Organization (WHO) Group 1 Pulmonary Hypertension (PH) [pulmonary arterial hypertension (PAH)] in any of the following subtypes:

  1. Idiopathic
  2. Heritable
  3. Drug/toxin-induced or connective tissue disease (CTD)-associated PAH
  4. Congenital heart disease-related with simple systemic-to-pulmonary shunt at least 1 year following repair.

• PAH diagnosis for at least 3 months.

• Participants must be on stable PH therapy consisting of up to 2 medications from the following classes:

  1. Endothelin receptor antagonists (eg, ambrisentan, bosentan, macitentan)
  2. Phosphoesterase type 5 inhibitors (eg, sildenafil, tadalafil)
  3. Guanylate cyclase stimulator (eg, riociguat)

• No change in PH medications (eg, ambrisentan, bosentan, macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 30 days prior to Screening.

• No change in long-term diuretic use or dosage for at least 30 days prior to Screening.

• Body Mass Index (BMI) within the range 18.0-37.0 kg/m^2 (inclusive).

• Male participants: Male participants who are not sterile and have female partners of childbearing potential, must be using effective contraception from Day 1 to at least 90 days after the last dose of study drug.

• Female participants: Women must be postmenopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile, (ie, post-tubal ligation for at least 12 months) or using highly effective contraception methods (ie, methods that alone or in combination achieve <1% unintended pregnancy rates per year when used consistently and correctly) from Day 1 to at least 90 days after the last dose of study drug.

• Male participants with pregnant or non-pregnant woman of childbearing potential partner must use a condom in order to avoid potential exposure to embryo/fetus.

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.

Exclusion Criteria:

• History of PH other than idiopathic, hereditary, drug/toxin-induced, repaired simple congenital heart disease, or CTD-associated PAH (eg, complex, congenital heart disease-associated PAH, portal hypertension-associated PAH, PH belonging to Groups 2 through 5).
• Allergy, or documented hypersensitivity or contraindication, to TPIP or Treprostinil or mannitol (an excipient of the TPIP formulation).
• Any known ventricular or supraventricular tachyarrhythmia except for paroxysmal atrial fibrillation and any symptomatic bradycardia.
• History of heart disease including left ventricular ejection fraction (LVEF) ≤ 40% or clinically significant valvular, constrictive, or symptomatic atherosclerotic heart disease (eg, stable angina, myocardial infarction, etc).
• Participation in a cardio-pulmonary rehabilitation program within 1 month of Screening Visit.
• Evidence of thromboembolic disease as assessed by ventilation-perfusion (VQ) scan, pulmonary angiography, or pulmonary computed tomography (CT) scan.
• Active liver disease or hepatic dysfunction.
• History of HIV infection.
• Established diagnosis of hepatitis B viral infection, or positive for hepatitis B surface antigen (HBsAg) at the time of Screening.
• Established diagnosis of hepatitis C viral infection at the time of screening.
• Active and current symptomatic coronavirus disease 2019 (COVID-19) or previous severe disease and/or hospitalization due to COVID-19.
• Use of live attenuated vaccines within 30 days of the Screening Visit.
• Participants with Down's Syndrome.
• History of abnormal bleeding or bruising.
• History of solid organ transplantation.
• Known or suspected immunodeficiency disorder, including history of invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency, or prolonged infections suggesting an immune compromised status, as judged by the Investigator.
• History of alcohol or drug abuse within 6 months prior to Screening.
• Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6-minute walk test (eg, angina pectoris, claudication, musculoskeletal disorder, need for walking aids).
• Participants with current or recent (past 30 days) lower respiratory tract infection.
• History of malignancy in the past 5 years, with exception of completely treated in situ carcinoma of the cervix and completely treated non-metastatic squamous or basal cell carcinoma of the skin.
• Change in PH medication (endothelin receptor agonists, phosphoesterase type 5 inhibitors, and guanylate cyclase stimulators or diuretics) between Screening and Baseline.
• Have participated in any other interventional clinical studies within 30 days prior to Screening.
• Current use of cigarettes (as defined by Centers for Disease Control and Prevention) or e-cigarettes.
• Participants who currently inhale marijuana (recreational or medical).
• Pregnant or breastfeeding.

Note: Other inclusion/exclusion criteria may apply.