TPIP Tolerable Over 2 Years in PH-ILD, with Colin Church, MBBS, PhD

Inhaled treprostinil established pulmonary vascular disease in interstitial lung disease (ILD) as a treatable target, but patients with pulmonary hypertension associated with ILD (PH-ILD) can still face progressive exercise limitation and clinical worsening on existing inhaled prostacyclin therapy. Treprostinil palmitil inhalation powder (TPIP) is a lung-retained prodrug, linking treprostinil to a 16-carbon chain by an ester bond so endogenous esterases convert it to active treprostinil within the lung over time, intended to support once-daily dosing.

In the 16-week, phase 2, placebo-controlled lead-in trial (NCT05176951), TPIP was generally well tolerated with a safety profile consistent with inhaled prostacyclin therapy and reduced the proportion of patients with clinical worsening versus placebo.¹ This 24-month, phase 2 open-label extension (NCT05649722) enrolled 31 patients who completed the lead-in trial, 23 who had received TPIP and 8 who had received placebo, to evaluate long-term safety, tolerability, and effectiveness.²

Of the 16 patients who completed the 24-month extension, 83.9% of all enrollees maintained the maximum 640-µg once-daily dose, and compliance was 97.2%. Cough was the most common adverse event (AE), occurring in 29% of patients, but every cough event was mild and none led to dose reduction or discontinuation.²

Serious adverse events occurred in 71% of patients, and 19.4% discontinued due to treatment-emergent AEs, though no serious AEs, deaths, or discontinuations were considered treatment-related. There were 6 deaths during the 24-month extension, none attributed to study treatment.²

Colin Church, MD, consultant in pulmonary vascular and respiratory medicine at Queen Elizabeth University Hospital in Glasgow, led this open-label extension analysis. Church spoke with HCPLive at the CHEST 2026 Annual Meeting in Phoenix about what the 2-year tolerability data mean for patients already carrying a heavy PH-ILD treatment burden.

HCPLive: What unmet need remains in PH-ILD despite inhaled treprostinil being available?

Colin Church, MD: Inhaled treprostinil was a major advance because it demonstrated pulmonary vascular disease in ILD is treatable. But substantial unmet need remains. These are very sick patients with progressive lung and vascular disease, ongoing exercise limitation, and significant clinical worsening. We therefore need therapies that are effective, practical for patients to take long term, and ideally address more than pulmonary vascular tone alone. A once-daily inhaled treatment could be particularly attractive in a population already carrying a considerable treatment burden.

HCPLive: What's different about treprostinil palmitil as a molecule?

Colin Church, MD: The important difference is TPIP is not simply another formulation of treprostinil. Treprostinil palmitil is a prodrug in which treprostinil is linked by an ester bond to a 16-carbon chain. After inhalation, it remains within the lung and is progressively converted to active treprostinil by endogenous enzymes, or esterases, effectively making the lung a reservoir and giving prolonged local exposure with less of the rapid peak-and-trough pharmacology of conventional inhaled treprostinil. Phase 1 data showed treprostinil remained detectable 24 hours after TPIP dosing, supporting the rationale for once-daily administration. It is essentially a lung-retained prodrug designed to turn treprostinil into a once-daily inhaled therapy.

HCPLive: How tolerable was TPIP over 2 years?

Colin Church, MD: I think the reassuring message is that TPIP appeared reasonably well tolerated with prolonged exposure, recognizing the limitations of the study size. Compliance was 97.2%, and 83.9% of patients maintained the maximum 640-µg dose. Cough was the most common adverse event, occurring in 29%, but importantly all cough events were mild and none resulted in dose reduction or discontinuation. For a long-term inhaled prostanoid study in patients with advanced ILD, that is an encouraging tolerability signal.

HCPLive: How should clinicians interpret the serious adverse events reported in this study?

Colin Church, MD: This is really important. There was a high burden of serious events, but we have to interpret that in the context of the disease being studied rather than simply looking at the raw numbers. This is a significant disease with a sick population. Serious adverse events occurred in 71%, 45.2% experienced clinical worsening, 51.6% had an acute ILD exacerbation, and 6 patients died. Crucially, none of the serious adverse events, deaths, or discontinuations were considered related to TPIP by the investigators. So I wouldn't dismiss those events, because they illustrate just how vulnerable this population is. But equally, there isn't a signal from this study suggesting TPIP was driving them.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools. Relevant disclosures include Insmed.

References

1. Church C, Molina-Molina M, Arias-Guillén M, et al. A phase 2 study of the safety and tolerability of treprostinil palmitil inhalation powder in patients with pulmonary hypertension associated with interstitial lung disease. Pulm Circ. 2026;16(2):e70322. doi:10.1002/pul2.70322

2. Church C, Molina M, Saggar R, et al. An open-label extension study of treprostinil palmitil inhalation powder (TPIP) in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). Presented at: CHEST 2026 Annual Meeting; October 18-21, 2026; Phoenix, AZ.