Inhaled Treprostinil Slows FVC Decline in Idiopathic Pulmonary Fibrosis

The Persistent Challenge of Halting Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis remains a relentlessly progressive and ultimately fatal interstitial lung disease, characterized by an irreversible decline in lung function where a 5 percent decrease in forced vital capacity over 12 months doubles mortality risk [1, 2]. While current oral antifibrotic therapies, such as nintedanib and pirfenidone, slow the annual decline in forced vital capacity by 44 to 57 percent, they do not halt disease progression or offer a cure [3, 1]. Furthermore, the clinical community has increasingly emphasized the need for therapies that not only preserve lung volume but also translate into meaningful improvements in how patients feel, function, and survive [4]. Recent investigations have explored alternative pharmacological pathways, including inhaled prostacyclin agonists (vasodilatory medications that mimic endogenous prostaglandins), which previously improved 6-minute walk test distances in patients with pulmonary hypertension secondary to interstitial lung disease [3, 5]. A new study now offers fresh insights into whether delivering inhaled treprostinil directly to the lungs can alter the primary fibrotic disease course [6].

Evaluating Inhaled Treprostinil in a Phase 3 Cohort

Preclinical data and clinical observation suggest that inhaled treprostinil may treat idiopathic pulmonary fibrosis (IPF) through a direct antifibrotic mechanism, rather than solely acting as a vasodilator. To evaluate this premise, researchers conducted a phase 3, double-blind trial funded by United Therapeutics (TETON-2 ClinicalTrials.gov number, NCT05255991). Patients with IPF were randomly assigned to receive either inhaled treprostinil or a matching placebo. The treatment regimen required patients to administer 12 breaths four times daily over a continuous period of 52 weeks. The primary end point of the trial was the change from baseline in absolute forced vital capacity (FVC) at week 52, a standard measure of disease progression in fibrotic lung disease. To control for multiplicity (the statistical risk of false-positive results that arises when testing multiple outcomes simultaneously), the investigators analyzed secondary end points in a prespecified hierarchical order. These secondary end points included clinical worsening and acute exacerbation of IPF, each assessed in a time-to-event analysis (a statistical method that measures the duration until a specific clinical milestone occurs), alongside death by week 52. Additional secondary end points evaluated the change from baseline in the percentage of predicted FVC, quality of life, and the diffusing capacity of the lungs for carbon monoxide by week 52. Safety was also assessed throughout the trial to monitor adverse events associated with the inhaled therapy.

Patient Demographics and Baseline Characteristics

The researchers enrolled a total of 593 patients who underwent randomization and received at least one dose of their assigned treatment. This cohort was split nearly evenly, with 298 patients receiving inhaled treprostinil and 295 patients receiving the placebo. Retention is a critical factor in evaluating the tolerability of long-term inhaled therapies. By the end of the study period, 463 patients successfully completed the trial assessments through week 52. This final completion group included 224 patients in the treprostinil group and 239 patients in the placebo group. The baseline characteristics of the study population closely mirror the typical clinical demographic seen in practice for idiopathic pulmonary fibrosis. The mean age of the patients was 71.7 years, and the cohort was predominantly male, with 80.1 percent being men. At the start of the trial, the mean forced vital capacity (FVC) at baseline was 76.8 percent, indicating moderate baseline lung function impairment. From a clinical perspective, it is highly relevant that 75.4 percent of the patients were already receiving background antifibrotic therapy. This high rate of concurrent treatment allows physicians to evaluate the efficacy of inhaled treprostinil as an add-on therapy to standard-of-care oral medications, directly reflecting real-world prescribing patterns where combination regimens are increasingly common.

Primary and Secondary Efficacy Outcomes

The primary efficacy analysis demonstrated that inhaled treprostinil significantly preserved lung volume compared to placebo. At week 52, the median change in forced vital capacity (FVC) was -49.9 ml (95% confidence interval [CI], -79.2 to -19.5) in the treprostinil group, indicating a slowed rate of lung function decline. In contrast, the median change in FVC at week 52 was -136.4 ml (95% CI, -172.5 to -104.0) in the placebo group. This resulted in a clinically meaningful between-group difference in the change in FVC at week 52 of 95.6 ml (95% CI, 52.2 to 139.0; P<0.001). For practicing physicians, this preservation of nearly 100 ml of lung capacity over one year represents a tangible delay in disease progression. Beyond preserving lung volume, the therapy also reduced the risk of overall disease progression. Clinical worsening occurred in 81 patients (27.2%) in the treprostinil group and 115 patients (39.0%) in the placebo group, yielding a hazard ratio of 0.71 (95% CI, 0.53 to 0.95; P=0.02). Despite these improvements, the researchers noted that no substantial between-group difference in the time to IPF exacerbation was observed. Because the trial utilized a prespecified hierarchical testing order (a strict sequence where testing stops as soon as one outcome fails to reach significance), no further inferences with regard to subsequent secondary end points were made. Consequently, outcomes such as quality of life and diffusing capacity could not be formally evaluated for statistical significance. Overall, the trial data establish a clear therapeutic benefit for this intervention. In patients with IPF, inhaled treprostinil was associated with a smaller decline in FVC and fewer clinical-worsening events than placebo over a period of 52 weeks. For clinicians managing this relentlessly progressive disease, these findings indicate that adding an inhaled prostacyclin analogue can meaningfully alter the clinical trajectory and preserve respiratory function.

Safety Profile and Treatment Discontinuation

When evaluating any inhaled therapy for a chronic respiratory condition, tolerability is a primary clinical concern. In this trial, the most common adverse event was cough, which was reported in 48.3% of the patients in the treprostinil group and 24.1% of those in the placebo group. For practicing physicians, this high incidence of cough highlights the need for proactive patient counseling and symptom management when initiating inhaled prostacyclin therapy, as local airway irritation is a known pharmacological effect of the delivery method. The burden of adverse events directly influenced trial retention. Discontinuation of treprostinil or placebo occurred in 33.6% and 24.7% of patients, respectively. When analyzing the causes for withdrawal, the researchers noted that approximately half of the patients who discontinued treatment cited adverse events as the primary reason. This attrition rate underscores the clinical challenge of balancing the lung-preserving benefits of inhaled treprostinil against its side effect profile, requiring careful patient selection and close monitoring to maintain long-term adherence.

References

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