Tiprelestat Versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH) (ATHENA)

A Phase II, Randomized, Double-Blind, Safety and Efficacy Study of Tiprelestat Versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)

The primary objective of this study is to compare the efficacy, safety, and tolerability of tiprelestat plus Standard of Care (SOC) compared with placebo plus SOC in patients with World Health Organization (WHO) functional class II-IV pulmonary arterial hypertension (PAH).

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Arterial Hypertension (PAH)
• Intervention / Treatment: Drug: Tiprelestat (5 mg); Drug: Tiprelestat (10 mg); Drug: Placebo (1 mL 0.9% saline solution)

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • The University of Arizona / Banner University Medical Center
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado (UCD) Anschutz
  • Massachusetts
    • Boston, Massachusetts, United States, 02138
      • Harvard University / Brigham and Women's Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02904
      • Brown University/Rhode Island Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults age 18 to 75 years.
2. Willingness to give written informed consent prior to any study-related procedures being performed and to be able to adhere to the study restrictions and examination schedule.
3. Diagnosis of WHO Group I PAH.
4. WHO functional class II - IV despite optimized treatment SOC, with 1 or more modalities including phosphodiesterase 5 (PDE5) inhibitor, soluble guanylate cyclase stimulator (sGCS), endothelin receptor antagonist (ERA), and/or a prostacyclin analogue or receptor agonist (SC/inhaled/PO) (see #5), as well as Sotatercept (see #6).
5. On stable doses of PDE5 inhibitor, ERA, sGCS, or prostacyclin analogue/receptor agonist for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of baseline dose during the duration of the study is allowed per medical practice.
6. On stable doses of Sotatercept therapy for at least 6 months prior to screening, and intended to be continued during the duration of the study.
7. Screening right heart catheterization mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest; pulmonary wedge pressure (PAWP) ≤ 15 mmHg or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg; AND pulmonary vascular resistance (PVR) ≥ 400 dynes•sec/cm5 (5 Wood Units).
8. If participant is of childbearing potential, willing to use adequate methods of contraception throughout the course of the study. If participant is of childbearing potential (a participant < 55 years of age who has not been postmenopausal for ≥ 5 years or who has not had a bilateral salpingectomy, hysterectomy and/or oophorectomy), need to employ two reliable means of contraception which may include surgical sterilization, barrier methods, spermicidals, intrauterine devices, and/or hormonal contraception, unless the participant chooses abstinence (to avoid heterosexual intercourse completely). If a participant chooses abstinence, then a second reliable means of contraception is not needed.
9. 6MWD ≥100 and ≤500 meters at screening.
10. Willing to adhere to study restrictions and examination schedule.

Exclusion Criteria:

1. Diagnosis of WHO Group 2 - 5 Pulmonary Hypertension.
2. Participation in another clinical trial, or experimental use, involving a PAH investigational drug or device within the last 3 months.
3. Total lung capacity (TLC) < 60% predicted; if TLC is ≥ 60% and < 70% predicted, high resolution computed tomography (HRCT) must be available to exclude significant interstitial lung disease.
4. FEV1 / FVC < 70% predicted and FEV1 < 60% predicted.

5. Significant left-sided heart disease (based on screening Echocardiogram):

   1. Moderate or severe aortic or mitral valve disease
   2. Diastolic dysfunction ≥ Grade II
   3. LV systolic function < 45%
   4. Pericardial constriction
   5. Restrictive cardiomyopathy
   6. Significant coronary disease with demonstrable ischemia
6. Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min.
7. Current atrial arrhythmias not under optimal control.
8. Uncontrolled systemic hypertension: SBP > 160 mmHg or DBP > 100mmHg.
9. Severe hypotension: SBP < 80 mmHg.
10. Pregnant or breast-feeding.
11. Psychiatric, addictive, or other disorders that compromise the patient's ability to provide informed consent, to follow study protocol, and adhere to treatment instructions.
12. Known allergy or hypersensitivity to tiprelestat.
13. Moderate to severe hepatic dysfunction with a Child Pugh score >10.
14. Hyperkalemia defined as Potassium > 5.1 mEq/L at screening.
15. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to screening or planned during the study. Subjects who are already stable in the maintenance phase of an exercise program which will continue for the duration of the study are eligible.
16. Known active infection requiring antibiotic, antifungal, or antiviral therapies. Patients may be rescreened at physician discretion after the resolution of infection and discontinuation of antibiotic, antifungal, or antiviral therapies.
17. Co-morbid conditions that would impair a patient's exercise performance and ability to assess WHO functional class, including but not limited to chronic low-back pain or peripheral musculoskeletal problems, other comorbidities expected to alter the patient's clinical course (i.e. active cancer; >3 comorbidities e.g., obesity, systemic HTN, diabetes).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tiprelestat (5 mg); Participants receive tiprelestat injection daily for 168 days.	Drug: Tiprelestat (5 mg); 5 mg of tiprelestat in 1 mL saline administered as a daily subcutaneous injection for 168 days.; Other Names: Elafin
Experimental: Tiprelestat (10 mg); Participants receive tiprelestat injection daily for 168 days.	Drug: Tiprelestat (10 mg); 10 mg of tiprelestat in 1 mL saline administered as a daily subcutaneous injection for 168 days.; Other Names: Elafin
Placebo Comparator: Placebo (1 mL 0.9% saline solution); Participants receive placebo injection (matching tiprelestat) daily for 168 days.	Drug: Placebo (1 mL 0.9% saline solution); Matching 1 mL 0.9% saline solution administered as a daily subcutaneous injection for 168 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pulmonary Vascular Resistance (PVR)	PVR is calculated based on direct measurements during the right heart catheterization (RHC) procedure. PVR = (mPAP - PAWP) / CO, where mPAP is the mean pulmonary artery pressure, PAWP is the pulmonary wedge arterial pressure, and CO is the cardiac output. These cardiac measures are also obtained from right heart catheterization. PVR is measured in Wood units (WU) or dynes (dynes*sec/cm5), and higher values are associated with more severe disease. Normal range for PVR is 1-3 WU (80-240 dynes*sec/cm5) and can be as high as 30 WU (2,400 80-240 dynes*sec/cm5) in disease.	Baseline to week 24

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Michigan
• Investigators: Principal Investigator: Roham T Zamanian, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): February 1, 2030
• Study Completion (Estimated): March 1, 2030

Study Registration Dates

• First Submitted: May 15, 2026
• First Submitted That Met QC Criteria: May 15, 2026
• First Posted (Actual): May 22, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: PAH; pulmonary arterial hypertension; tiprelestat; elafin
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Pharmaceutical Preparations; Crystalloid Solutions; Isotonic Solutions; Solutions; Proteinase Inhibitory Proteins, Secretory; Elafin; Saline Solution
• Other Study ID Numbers: 84755; UG3HL180990 (U.S. NIH Grant/Contract); U24HL180994 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No