A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter, Parallelgroup Study to Evaluate the Efficacy and Safety of Treprostinil Palmitil Inhalation Powder in Participants with Pulmonary Hypertension Associated with Interstitial Lung Disease

The primary objective of this study is to evaluate the effect of treprostinil palmitil inhalation powder (TPIP) compared with placebo on exercise capacity in patients with pulmonary hypertension associated with interstitial lung disease. Exercise capacity serves as a critical functional endpoint reflecting cardiopulmonary reserve and disease severity in this patient population, providing clinically meaningful assessment of therapeutic efficacy.

The secondary objectives are:

• To evaluate the effect of TPIP compared with placebo on clinical worsening, a composite endpoint encompassing disease progression events relevant to patient prognosis.

• To evaluate the effect of TPIP compared with placebo on major morbidity and mortality, addressing hard clinical outcomes of therapeutic intervention.

• To evaluate the effect of TPIP compared with placebo on NT-proBNP levels, a validated biomarker of cardiac stress and hemodynamic burden in pulmonary hypertension.

• To evaluate the effect of TPIP compared with placebo on trough exercise capacity, assessing functional status at the end of dosing interval to evaluate sustained therapeutic effect.

• To evaluate the effect of TPIP compared with placebo on exercise capacity at additional timepoints.

• To evaluate the effect of TPIP compared with placebo on overall symptoms and associated physical activities, capturing patient-reported functional limitations and symptom burden.

• To evaluate the pharmacokinetics of TP and TRE in plasma, characterizing systemic exposure and drug disposition following inhalation administration.

This clinical trial enrolled a total of **110 participants** diagnosed with **pulmonary hypertension** associated with **interstitial lung disease** (WHO Group 3). The study population included both **male and female participants** aged **18 years and older**. Participants were required to have confirmed fibrotic interstitial lung disease documented by CT scan and pulmonary hypertension verified by **right heart catheterization** with specific hemodynamic criteria, including **mean pulmonary artery pressure** greater than 20 mmHg, **pulmonary capillary wedge pressure** of 15 mmHg or less, and **pulmonary vascular resistance** of at least 4 Wood Units. Exercise capacity was assessed through **six-minute walk distance** testing, with participants demonstrating a walking distance between 100 and 500 meters. The trial population included individuals who may have been receiving chronic medications for their underlying disease, such as **antifibrotics**, **immunomodulators**, or **immunosuppressants**, as well as **PDE5 inhibitors**, provided these treatments were stable for a specified period prior to enrollment. The study included vulnerable populations and required participants to be capable of providing informed consent and adhering to protocol requirements.

This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group clinical trial designed to evaluate the efficacy and safety of **treprostinil palmitil inhalation powder** in participants with **pulmonary hypertension** associated with **interstitial lung disease**. The trial investigates **WHO Group 3 pulmonary hypertension**, including conditions such as idiopathic interstitial pneumonia, chronic hypersensitivity pneumonitis, connective tissue disease-associated interstitial lung disease, and combined pulmonary fibrosis and emphysema. The primary objective is to assess the effect of treprostinil palmitil inhalation powder compared with placebo on exercise capacity. The trial employs a parallel-group design in which participants are randomly assigned to receive either the active investigational medicinal product or placebo.

The investigational medicinal product consists of **treprostinil palmitil** administered as an **inhalation powder** via a Plastiape capsule-based dry powder inhaler device. The active substance is of chemical origin and is delivered in various dosage strengths including 80 micrograms, 160 micrograms, 320 micrograms, and 640 micrograms. The maximum daily dose is 1280 micrograms, with a maximum total dose of 215,040 micrograms over a treatment period of 24 weeks. Placebo consists of inhalation powder capsules matching one of the four dosage strengths of the active product. The route of administration for all formulations is via inhalation.

Eligible participants include males and females aged 18 years or older with a confirmed diagnosis of WHO Group 3 pulmonary hypertension associated with fibrotic interstitial lung disease. Diagnosis must be supported by a centrally reviewed computed tomography scan performed at screening or within the preceding 12 months. Pulmonary hypertension must be confirmed by **right heart catheterization** at screening or within 12 months prior to screening, demonstrating mean pulmonary arterial pressure greater than 20 mmHg, **pulmonary capillary wedge pressure** of 15 mmHg or less, and **pulmonary vascular resistance** of at least 4 Wood Units. Participants must demonstrate a **6-minute walk distance** between 100 and 500 meters at two tests performed at screening at least 4 hours apart, with a difference of 15 percent or less between the two distances. Participants receiving chronic medication for underlying disease or phosphodiesterase-5 inhibitors must be on treatment for at least 90 days and on a stable dose for at least 30 days prior to screening. Participants of childbearing potential must use appropriate contraceptive methods consistent with local regulations.

The primary endpoint is the change in 6-minute walk distance measured at peak exposure from baseline to Week 24. Secondary endpoints include time from randomization to first clinical worsening over 24 weeks, time from randomization to first major morbidity or mortality event over 24 weeks, change in **N-terminal pro-B-type natriuretic peptide** plasma concentration from baseline over 24 weeks, proportion of participants with improvement in N-terminal pro-B-type natriuretic peptide levels over 24 weeks, change in 6-minute walk distance measured at trough exposure from baseline to Week 22, change in 6-minute walk distance measured at peak exposure from baseline over 20 weeks, and change in Living With Pulmonary Fibrosis total symptom domain score from baseline over 24 weeks. Plasma concentrations of treprostinil palmitil and treprostinil will also be assessed.

The trial duration is estimated to extend from February 2026 to December 2028. Participant involvement spans approximately 24 weeks of treatment. The study includes a screening visit to assess eligibility and confirm diagnosis through appropriate diagnostic procedures. Following enrollment, participants attend scheduled follow-up visits for administration of study medication, assessment of efficacy endpoints, safety monitoring, and collection of pharmacokinetic samples. The end-of-study visit occurs at Week 24 or upon early termination. Early termination from the study may occur due to adverse events, withdrawal of consent, protocol violations, loss to follow-up, or at the discretion of the investigator if continued participation is not in the best interest of the participant.

The experimental medication used in this clinical trial is **treprostinil palmitil inhalation powder**, also known by its synonyms hexadecyl treprostinil and treprostinil hexadecyl ester. The active substance is of chemical origin. The investigational medicinal product is supplied as an **inhalation powder** in four different **dosage strengths**: 80 µg, 160 µg, 320 µg, and 640 µg. The product is administered via the **inhalation route** using a **Plastiape capsule-based dry powder inhaler device** (RS01 Monodose Inhaler Model 7), which is CE-marked and manufactured in Italy. The sponsor product code for this investigational medicinal product is INS1009.

The **maximum daily dose** of treprostinil palmitil inhalation powder is **1280 µg**. The **maximum total dose** administered over the treatment period is **215040 µg**. The **maximum treatment period** is **24 weeks**. The investigational medicinal product is manufactured under Manufacturing and Importation Authorization MIA (IMP) 20377.

The **placebo** used in this clinical trial consists of inhalation powder capsules that match the appearance of the active investigational medicinal product. The placebo is available in formulations corresponding to the four dosage strengths of treprostinil palmitil inhalation powder: 80 µg, 160 µg, 320 µg, and 640 µg. The placebo is administered via inhalation using the same delivery device as the active treatment. The placebo is manufactured under the same Manufacturing and Importation Authorization as the active investigational medicinal product.

Efficacy will be assessed using the change in 6-minute walk distance (6MWD) measured at peak exposure from baseline to week 24 as the primary endpoint. The 6MWD will be evaluated at screening with two tests performed at least 4 hours apart, with the difference between the two distances not exceeding 15 percent. Additional efficacy parameters include time from randomization to first clinical worsening over 24 weeks and time from randomization to first major morbidity or mortality event over 24 weeks. Changes in NT-proBNP plasma concentration from baseline over 24 weeks will be measured, along with the proportion of participants with improvement in NT-proBNP levels over 24 weeks. The change in 6MWD measured at trough exposure from baseline to week 22 and the change in 6MWD measured at peak exposure from baseline over 20 weeks will also be assessed. Patient-reported outcomes will be evaluated through the change in Living With Pulmonary Fibrosis (L-PF) total symptom domain score from baseline over 24 weeks. Plasma concentrations of treprostinil palmitil and treprostinil will be measured to support efficacy assessments.