Dual Prostacyclin Rescue Inhaler Clears IND but Faces No Precedent and Payer Walls

FDA Clears United Therapeutics' Treprostinil-Iloprost SMI for Clinical Trial

United Therapeutics Corporation has received FDA clearance under its Investigational New Drug (IND) application to proceed with a clinical trial for Treprostinil-Iloprost SMI. This investigational therapy, combining two potent prostacyclin analogues, treprostinil and iloprost, is designed as a use-as-needed inhaled treatment via a soft mist inhaler for episodic symptom relief in pulmonary arterial hypertension (PAH) patients experiencing flare-ups. The initial phase 1, open-label, single ascending dose study will assess safety, tolerability, and pharmacokinetics in healthy volunteers, with a subsequent phase 2 study in PAH patients anticipated in 2027.

• United Therapeutics secured FDA clearance for its Investigational New Drug (IND) application for Treprostinil-Iloprost SMI, marking a crucial step towards developing a novel, as-needed inhaled therapy for Pulmonary Arterial Hypertension (PAH). This therapy aims to address a significant unmet need by providing episodic symptom relief for patients experiencing acute flare-ups, complementing their existing prostacyclin maintenance regimens.
• Treprostinil-Iloprost SMI is a unique combination of two potent prostacyclin analogues, treprostinil and iloprost, delivered via a soft mist inhaler. This innovative approach is designed for pro re nata (PRN) use, offering flexibility and targeted relief for PAH patients who currently lack specific therapies for acute symptomatic moments, potentially improving their quality of life.
• The program will commence with a Phase 1, open-label, single ascending dose study to evaluate the safety, tolerability, and pharmacokinetics of Treprostinil-Iloprost SMI in healthy volunteers. Following successful completion of this initial phase, United Therapeutics plans to initiate a Phase 2 study in patients with PAH in 2027, outlining a clear progression towards further clinical investigation and potential market introduction.

Why PAH Patients Need As-Needed Symptom Relief

Recent literature describes pulmonary arterial hypertension (PAH) as a progressive disease with high morbidity and mortality despite therapies targeting the endothelin, nitric oxide/cyclic guanosine monophosphate, and prostacyclin pathways. Risk stratification at diagnosis and follow-up guides initial dual or triple combination therapy, with escalation for patients remaining at intermediate or high risk. Key unmet needs center on underutilization of guideline-recommended combinations, refractory and high-risk disease, and populations with worse outcomes or limited drug access.

• High-risk, advanced and refractory PAH requiring triple therapy with parenteral prostacyclin: The 2022 European Society of Cardiology/European Respiratory Society guidelines recommend initial triple-combination therapy including parenteral prostacyclin analogues for high-risk patients after diagnosis when estimated 1-year mortality is more than 20%, and dual-combination therapy with an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor for all other classic PAH patients. Real-world data from the Pulmonary Hypertension Association Registry in 1,019 patients with incident PAH showed initial monotherapy in 344 [33.8%], dual therapy in 557 [54.7%], and triple therapy in 118 [11.6%], highlighting underutilization. The multicentric TripleTRE phase IV trial will enrol 110 patients with intermediate-high risk of death at PAH diagnosis randomized 1:1 to initial double-oral treatment or upfront triple combination including parenteral treprostinil, with primary end-point achievement of low-risk status between week 24 and 48.

• Intermediate-risk PAH requiring refined four-strata assessment and earlier escalation: Follow-up assessment with a new 4-strata classification splits intermediate risk on the basis of three noninvasive parameters, where changes from intermediate-high to intermediate-low risk have been shown to be associated with a better prognosis. In a retrospective chart review of 350 patient records, 62% were intermediate-high risk, 33% intermediate-low risk and 3% low risk at parenteral prostacyclin initiation, improving to 38%, 53%, and 8% at follow-up at median 3.0 months. Treatment escalation includes addition of a prostacyclin receptor agonist or switching a phosphodiesterase-5 inhibitor to a soluble guanylate cyclase stimulator for intermediate-low risk and triple-combination therapy with parenteral prostacyclin analogues already for intermediate-high risk.

• Patients not reaching goals on phosphodiesterase-5 inhibitor-based dual therapy: Switching from a phosphodiesterase-5 inhibitor to the soluble guanylate cyclase stimulator riociguat may provide clinical benefit in patients not reaching treatment goals and at intermediate risk. A response was defined as absence of clinical worsening and at least two of 6-min walk distance increase by 10% or ≥ 30 m, World Health Organization functional class I/II, or N-terminal prohormone of brain natriuretic peptide reduction of ≥ 30% at Week 24 in RESPITE and REPLACE, where no baseline threshold value of cyclic guanosine monophosphate, asymmetric dimethylarginine, or growth/differentiation factor 15 provided a good likelihood of predicting response.

• Connective tissue disease-associated PAH with worse survival and compound phenotypes: Especially for systemic sclerosis, connective tissue disease-associated PAH has worse long-term survival than idiopathic or familial PAH, with cardiac involvement, interstitial lung disease and predisposition to thromboembolism leading to multiple mechanisms as well as precapillary pulmonary vasculopathy. In the combined OPUS/OrPHeUS dataset of 1192 patients with connective tissue disease-associated PAH and 2498 patients with idiopathic/heritable PAH newly initiating macitentan, 69.3% and 61.2% were in World Health Organization functional class III/IV, median 6-min walk distance was 279 and 289 m, and 65.2% and 58.1% received macitentan as combination therapy, with Kaplan-Meier survival at 1 year of 90.6% and 90.5%.

• Populations with limited access, delayed diagnosis, genetic risk, and need for disease-modifying pathways: Prostacyclin analogues are not marketed in India, where inhaled iloprost 2.5 μg six times daily as add-on therapy in 14 patients with group 1 PAH showed median increase of 31% in 6-minute walk test distance, median increase of 45% in right ventricular fractional area change, median increase of 27% in tricuspid annular peak systolic excursion and median decrease of 36.7% in N-terminal pro-brain natriuretic peptide levels. Delayed diagnosis >3 months versus ≤3 months was associated with worse outcome and lower event-free rate, while men had larger right heart size than women but tricuspid annular plane systolic excursion divided by systolic pulmonary artery pressure showed no significant sex differences. Novel approaches target reversal of pulmonary vascular remodeling, including sotatercept as a fusion protein that binds ligands of the transforming growth factor-β superfamily, inhaled seralutinib with promising phase 2 results, and glucagon-like peptide-1 receptor agonists attenuating severity of pulmonary hypertension in experimental models.

The Foundation of Treprostinil-Iloprost SMI: Known Safety

Treprostinil is a stable prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity, with major pharmacological actions including vasodilatation of the pulmonary and systemic vascular beds, inhibition of platelet aggregation and inhibition of smooth muscle cell proliferation. Common side effects of treprostinil therapy include headache, flushing, jaw pain, diarrhea, and for subcutaneous administration, infusion site pain or reaction. Pain at the infusion site has been a major drawback of subcutaneous treprostinil, hampering dose titration and leading to an 8-10% discontinuation rate, while in 860 PAH patients treated with subcutaneous treprostinil for up to 4 yrs, 199 (23%) discontinued due to adverse events. In the INSPIRE Phase 3 open-label trial in 121 PAH patients receiving Yutrepia (dry-powder formulation of treprostinil), 29 patients discontinued from the trial with the most common reason being adverse events, and the most common adverse events were cough, headache, upper respiratory tract infection, dyspnea, dizziness, throat irritation, diarrhea, chest discomfort, fatigue, and nasopharyngitis, most considered treatment-related though mild to moderate in severity. Inhaled treprostinil in children was discontinued in 4 patients because of symptoms including cough and bronchospasm (n = 3) and progression of PAH (n = 1), with mild side effects including cough (n = 9) and sore throat (n = 6) not requiring discontinuation, while oral treprostinil significantly improved 6-minute walk distance with a mean difference of 13.13 m but showed increased risk of adverse events leading to discontinuation (OR = 4.39).

Inhaled dry-powder formulations show airway-related tolerability signals that are dose-dependent and influenced by titration. In LTI-101, a phase 1 study of LIQ861 at 25, 50, 75, 100, 125, and 150 mcg in 57 subjects, all doses were generally well-tolerated with no deaths, serious adverse events, or dose-limiting toxicities, and the most frequently reported treatment-emergent adverse events related to study drug were coughing and throat irritation, reported more frequently at higher dose levels but all assessed as mild in severity. With treprostinil palmitil inhalation powder (TPIP), 70.8% (n = 17/24) of TPIP-treated participants in the single-dose phase experienced a treatment-emergent adverse event, with the most common events (≥20%) being cough (45.8%), dizziness (29.2%), and throat irritation (20.8%), while in the multiple-dose phase 83.3% (n = 10/12) experienced an event including cough (58.3%), headache (50.0%), nausea (33.3%), chest discomfort (33.3%), and dizziness (25.0%), with most events mild and no severe or serious events. In a retrospective single-center case series of 22 patients initiated on Yutrepia between June and December 2025, airway-specific adverse events were documented in 8 of 22 patients (36.4%; 95% CI: 19.7%-57.0%), with shortness of breath in 5 of 22 (22.7%) and cough in 3 of 22 (13.6%), no airway-related dose modifications or discontinuations were documented, while overall 54.5% of patients experienced an adverse event, 40.9% required dose modification, and 36.4% discontinued treatment because of an adverse event. Participants whose doses were titrated from TPIP 112.5 µg QD to 225 µg QD experienced fewer events than those who received 225 µg QD at initiation (66.7% vs 100.0%), and slow, cautious up-titration is generally associated with better long-term outcomes.

Iloprost (ILO) is employed intravenously for the treatment of severe Raynaud phenomenon and digital ulcers in systemic sclerosis (SSc), and inhaled iloprost is also effective in PAH but requires multiple daily nebulizations up to 15 min each and may induce cough, flushing, jaw pain and headache. In 81 consecutive SSc patients on nifedipine treated with ILO infusion 1 day/week, 16/81 presented digital edema, 5 developed diarrhea, and 9 developed transient hypotension during infusion at 20 ml/h that ameliorated when the drug was withdrawn, with 10/16 edematous patients experiencing significant and painful digital swelling unlike patients in the fibrotic group (p < 0.0001), 11/16 reporting flushing and 7/16 headache always controlled with dose tapering below 10 ml/h, while in atrophic/fibrotic phase patients (65/81), 10 developed diarrhea and 24 hypotension at 20 ml/h that led to temporary withdrawal, and 23/65 experienced flushing and 8/65 headache all controlled with infusion reduction below 10 ml/h. Data suggest that calcium channel blockers should be transitorily stopped while using ILO and that in patients with digital edema, ILO infusion should be carefully employed after evaluation of patient's drug tolerance. In other settings, blood pressure-guided hourly inhalation of iloprost in 7 patients with precapillary pulmonary hypertension and right-side heart failure showed stable systemic pressures (66.1 ± 6.9 mm Hg at baseline and 69.1 ± 6.4 mm Hg immediately after inhalation therapy, P = 0.48), in 26 patients with Grade 2-4 frostbite treated with a 5-day iloprost protocol no serious adverse events were associated with iloprost, and in 14 group 1 PAH patients receiving inhaled iloprost 2.5 μg six times daily as add-on therapy the medications were well tolerated with minimal and transient side-effects with no deaths.

Measuring Success in Future Treprostinil-Iloprost SMI Trials

Studies of pulmonary arterial hypertension employ functional, hemodynamic, clinical worsening, survival, and safety endpoints. Phase 2, phase 3, and phase 4 trials combine exercise capacity with pulmonary vascular measurements, World Health Organization functional class, biomarkers, and adjudicated clinical events.

• Exercise capacity and dyspnea: change from baseline to the end of week 12 in the distance walked in 6 minutes, changes in exercise capacity assessed by the SMWT, 6-minute walk distance, score on the Borg dyspnea scale, and Borg dyspnea score.

• Hemodynamics and cardiac function: change in pulmonary vascular resistance, pulmonary vascular resistance at week 12 expressed as ratio of baseline, mean pulmonary artery pressure, cardiac index, evaluation of cardiopulmonary hemodynamics, and assessment of right ventricular function and Right Ventricle-Pulmonary Artery coupling including RV fractional area change, tricuspid annular plane systolic excursion, Tissue Doppler Imaging, cardiac magnetic resonance, invasive hemodynamic assessment, and cardiopulmonary exercise testing.

• Functional class, biomarkers, and risk stratification: World Health Organization functional class, N-terminal pro-brain natriuretic peptide levels, NT-proBNP, high sensitive troponin-T, high sensitive CRP, galectin-3, red blood cell distribution width and eGFR, European Society of Cardiology/European Respiratory Society baseline risk score, REVEAL risk score, REVEAL risk score 2.0, and REVEAL Lite 2.0 scores.

• Clinical worsening and survival composites: time to clinical worsening, time to first clinical failure event defined as a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response, time to first PAH hospitalization or death, one-year and five-year survival rates from admission to the pulmonary hypertension program until death or the end of follow-up, primary endpoint of death or lung transplantation, and secondary endpoint of death, lung transplantation or heart failure.

• Quality of life, safety, and tolerability: quality-of-life variables, health-related quality of life, safety and tolerability, safety, adverse events, serious adverse events, drug-related adverse events, adverse event leading to discontinuation, study discontinuation because of adverse events, syncope, peripheral oedema, dyspepsia, headache, hypotension, asymptomatic hypotension with systemic systolic blood pressure below 90 mmHg, and hepatic safety.

Treprostinil-Iloprost SMI in the Evolving PAH Combination Landscape

Recent trials in pulmonary arterial hypertension (PAH) focus on dual, triple, and add-on strategies built on endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin pathway agents. Investigational approaches include initial combination, sequential addition, single-tablet fixed-dose combinations, and novel disease-modifying agents added to background therapy.

• Endothelin receptor antagonist (ERA) plus phosphodiesterase type 5 inhibitor (PDE5i) dual therapy: Evaluated combinations include Bosentan combined with Sildenafil, Bosentan combined with Tadalafil, and Ambrisentan combined with Tadalafil, with 29 trials with 5 949 participants in network meta-analysis and nine studies with 1807 participants comparing combination versus either agent alone; the multicenter, double-blind, adaptive phase 3 A DUE study investigated macitentan and tadalafil FDC versus macitentan 10 mg and versus tadalafil 40 mg monotherapies with change in pulmonary vascular resistance (PVR) at week 16 as primary endpoint.

• Initial versus sequential addition strategies: In an event-driven, double-blind study, initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil was compared to ambrisentan or tadalafil monotherapy with first event of clinical failure as primary end point; ATHENA-1 evaluated addition of ambrisentan in PAH patients with a suboptimal response to current PDE5i monotherapy with change in PVR as primary endpoint at week 24; a prospective, double-blinded, randomized controlled study investigated oral tadalafil 40 mg as add-on to background ambrisentan after 16 weeks.

• Triple oral and prostacyclin pathway combinations: Approaches include phosphodiesterase-5 inhibitor plus endothelin receptor antagonist plus selexipag, an oral selective prostacyclin IP receptor agonist, evaluated in a high-risk idiopathic PAH case and recommended as triple oral combination therapy in case of insufficient response to oral combination therapy with endothelin receptor antagonist and phosphodiesterase 5 inhibitor; iloprost combined with low dose tadalafil was evaluated in adult congenital heart disease patients with severe PAH in sequential versus upfront regimens.

• Sotatercept added to background therapy: Sotatercept, a first-in-class activin signaling modulator, was evaluated in PULSAR, SPECTRA, STELLAR, ZENITH, and HYPERION across diverse PAH populations receiving maximal background therapy including double and triple therapy with endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and prostacyclin infusion therapy; SPECTRA was a phase 2a, single-arm, open-label, multicenter exploratory study by invasive cardiopulmonary exercise testing in World Health Organization functional class III patients on combination background therapy.

• Inhaled add-on therapies on optimized combination vasodilator therapy: Inhaled seralutinib, an inhaled kinase inhibitor, was evaluated in the phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled TORREY trial in patients receiving standard background therapy with change in PVR from baseline to 24 weeks as primary endpoint; inhaled treprostinil, a tricyclic benzindene prostacyclin analog, was introduced in nine patients already receiving combination therapy with assessment of acute hemodynamic effects during initial right heart catheterization and long-term effects at 3 months.

Pioneering On-Demand Relief for PAH Flare-Ups

The recent IND clearance for Treprostinil-Iloprost SMI signals a strategic move to address a distinct, yet often overlooked, aspect of pulmonary arterial hypertension (PAH) management: the need for rapid, on-demand relief during symptomatic flare-ups. While existing inhaled prostacyclin analogs like iloprost and treprostinil are cornerstones of chronic PAH therapy, improving patients' exercise capacity and functional class, their utility is primarily in sustained, daily treatment. These therapies often demand frequent inhalations throughout the day, with iloprost requiring up to nine daily doses and treprostinil four, posing significant challenges to patient adherence and overall quality of life due to the time commitment and device maintenance.

This investigational combination therapy, delivered via a soft mist inhaler, aims to carve out a new niche by providing acute symptomatic relief. The potential benefits for patients are substantial, offering a tool to manage sudden exacerbations without altering their foundational chronic regimens. This could lead to improved patient satisfaction and a reduction in the impact of acute symptoms on daily life, potentially improving overall disease management.

However, this innovative approach also comes with inherent considerations. The safety and tolerability of acutely combining two potent vasodilators, even if individually well-characterized, will need rigorous evaluation. Prostacyclin-related side effects such as headache, cough, and dizziness are common, and their combined acute impact is yet to be fully understood. Furthermore, while iloprost has demonstrated efficacy in chronic settings, it has also been associated with occasional bronchoconstriction, a risk that could be amplified in an acute, combined inhaled formulation, particularly for patients with underlying respiratory vulnerabilities. The clinical trial program will need to clearly define and demonstrate the efficacy of 'episodic symptom relief,' as this is a distinct endpoint from the sustained improvements typically measured in chronic PAH studies. Success in these areas could position Treprostinil-Iloprost SMI as a valuable complementary therapy, enhancing the comprehensive management of PAH and offering a new dimension of patient care.