Insmed Incorporated announced positive topline results from its Phase 2b study of treprostinil palmitil inhalation powder (TPIP), a once-daily inhaled therapy for pulmonary arterial hypertension (PAH) that achieved statistically significant improvements across all primary and secondary endpoints. The randomized, double-blind, placebo-controlled study demonstrated TPIP's potential to transform prostanoid therapy for this devastating rare disease.
Primary Endpoint Success Demonstrates Hemodynamic Improvement
The study met its primary endpoint with a 35% placebo-adjusted reduction from baseline in pulmonary vascular resistance (PVR), achieving a Least Squares mean ratio of 0.65 (95% CI: 0.54, 0.79; p<0.001). This hemodynamic improvement represents a clinically meaningful reduction in the elevated blood pressure within the pulmonary arteries that characterizes PAH.
"The statistically significant and clinically meaningful results shown with TPIP in pulmonary arterial hypertension mark a potential breakthrough for patients and the future of prostanoid therapy," said Gene Sullivan, M.D., Chief Product Strategy Officer of Insmed. "These unprecedented Phase 2b results unequivocally demonstrate TPIP's potential to be a highly effective and well-tolerated once-daily prostanoid therapy for the treatment of PAH across disease severities and background treatment regimens."
Secondary Endpoints Show Functional and Cardiac Benefits
TPIP demonstrated significant improvements in functional capacity and cardiac stress markers. The placebo-adjusted improvement in six-minute walk distance (6MWD) was 35.5 meters (95% CI: 11.2, 60.7; p=0.003), indicating enhanced exercise tolerance. Additionally, the therapy achieved a 60% placebo-adjusted reduction from baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) concentrations, a biomarker for cardiac stress, with an LS mean ratio of 0.40 (95% CI: 0.27, 0.59; p<0.001).
Notably, these results were assessed approximately 24 hours after administration, demonstrating sustained therapeutic benefit throughout the 24-hour dosing period and supporting TPIP's once-daily dosing regimen.
Study Design and Patient Population
The multicenter study was conducted at 44 sites globally and enrolled 102 patients randomized 2:1 to receive either TPIP (n=69) or placebo (n=33) for 16 weeks. Patients started at a dose of 80 µg once daily and were titrated up to their maximum tolerated dose or to the maximum allowable dose of 640 µg once daily over a three-week period.
Of the patients treated with TPIP, 84% titrated to at least 480 µg once daily (n=58) and 75% titrated to the maximum allowed dose of 640 µg once daily (n=52). The high dose tolerance suggests good patient acceptance of the therapy. Overall, 90% of patients receiving TPIP (n=62) and all patients receiving placebo completed the study.
Safety Profile Supports Continued Development
TPIP was well tolerated in the study. Treatment-emergent adverse events (TEAEs) occurred in 88.4% of patients who received TPIP versus 75.8% of patients who received placebo. Serious TEAEs were observed in 7.2% of patients who received TPIP versus 3.0% of patients who received placebo, and severe TEAEs were observed in 5.8% of patients who received TPIP versus 3.0% of patients who received placebo.
TEAEs leading to treatment discontinuation were experienced by 5.8% of patients taking TPIP, with none in the placebo arm. There were no deaths in the study. The most common TEAEs occurring more frequently with TPIP than placebo were cough (40.6% vs 21.2%), headache (31.9% vs 15.2%), fatigue (10.1% vs 3.0%), chest discomfort (8.7% vs 0.0%), and flushing (8.7% vs 3.0%).
Regulatory Path Forward and Phase 3 Planning
Based on these results, Insmed will immediately engage with the U.S. Food and Drug Administration regarding Phase 3 trial design for PAH. The company plans to initiate a Phase 3 trial in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD) before the end of 2025 and a Phase 3 trial in patients with PAH in early 2026.
"Today's outstanding results for TPIP represent more than a decade of hard work and the application of innovative chemistry intended to deliver a safe and effective, once-daily inhaled prostanoid therapy for patients with PAH, a devastating, progressive disease," said Martina Flammer, M.D., MBA, Chief Medical Officer of Insmed.
Long-term Extension Study Enrollment
All patients who completed the Phase 2b study were eligible to enroll in the long-term open-label extension, which will evaluate TPIP up to a maximum allowable dose of 1,280 µg once daily. Of the patients who completed the Phase 2b study (n=95), 95% enrolled in the open-label extension, indicating strong patient interest in continued treatment.
About TPIP and PAH
Treprostinil palmitil inhalation powder is a dry powder formulation of treprostinil palmitil, a treprostinil prodrug consisting of treprostinil linked by an ester bond to a 16-carbon chain. Developed entirely in Insmed's laboratories, TPIP is administered via a capsule-based inhalation device and represents a potentially differentiated prostanoid therapy.
PAH is a serious, progressive, rare disease affecting the blood vessels in the lungs, leading to high blood pressure in the pulmonary arteries. It is estimated that approximately 35,000 patients in the U.S., 40,000 patients in the EU5, and 15,000 patients in Japan have been diagnosed with the disease. Untreated, PAH can be debilitating and often fatal.
