• Patients with PH-ILD receiving mosliciguat vs. placebo had improved pulmonary vascular resistance, 6-minute walk distance and NT-proBNP.
• A smaller proportion of the mosliciguat vs. placebo group had cough.

Adults with pulmonary hypertension associated with interstitial lung disease receiving once-daily inhaled mosliciguat had a larger decrease in pulmonary vascular resistance at week 16 vs. placebo, according to phase 2 trial topline data.

These findings on mosliciguat (Roivant, Pulmovant), a potential first-in-class sGC activator, were simultaneously presented at the European Respiratory Society International Congress.

“Mosliciguat demonstrated improvements across multiple clinically relevant domains, including hemodynamics, exercise capacity and biomarkers of right ventricular strain,” Parth M. Rali, MD, FCCP, site principal investigator for the phase 2 PHocus study, told Healio.

“These findings support further investigation of mosliciguat as a potentially important addition to the PH-ILD treatment landscape,” Rali, also director of the Temple University Health System pulmonary embolism response team program and professor of thoracic medicine and surgery at the Lewis Katz School of Medicine at Temple University, said.

In the global, multicenter, double-blinded phase 2 PHocus trial, researchers analyzed 135 adults with PH-ILD to determine the impact of once-daily inhaled mosliciguat vs. placebo on pulmonary vascular resistance (PVR), 6-minute walk distance (6MWD) and NT-proBNP at week 16.

“ILD is a disabling disease, and close to 50% of those patients have pulmonary (hypertension) related to it,” Rali, also a member of Healio Pulmonology’s Peer Perspective Board, told Healio. “Currently, inhaled treprostinil is the only approved therapy for this disease state. Inhaled treprostinil in current form needs to be taken 4 times a day and often met with cough as a side effect.”

The mosliciguat group included 91 patients (mean age, 67.7 years; 52% women), and the placebo group included the remaining 44 patients (mean age, 68.3 years; 41% women).

From baseline to week 16, patients receiving mosliciguat vs. placebo had a significantly larger decrease in PVR (–51.3% vs. 6.6%; placebo-adjusted change = –56.3%; P < .0001).

“The magnitude of the PVR reduction was particularly notable,” Rali said.

During a Roivant-hosted webcast, Matt Gline, CEO of Roivant, said “this is the largest reduction in PVR from baseline ever observed in any pulmonary hypertension study.”

Additionally, PVR was reduced in all patients receiving mosliciguat, according to the webcast presentation.

The mosliciguat group continued to have a significantly greater decrease in PVR between baseline and week 16 vs. the placebo group in all studied subgroups: age (< 65 years or ≥ 65 years), sex, diffusing capacity of the lungs for carbon monoxide (< 40% or ≥ 40%), presence of emphysema, use of antifibrotic therapy, level of pulmonary fibrosis (low, medium, high), use of phosphodiesterase 5 inhibitor, PVR category (< 5 WU or ≥ 5 WU), PVR quartile, baseline 6MWD (≤ 350 m or > 350 m) and PH-ILD etiology (non-IPF, IPF, connective tissue disease-associated ILD, idiopathic interstitial pneumonia, chronic hypersensitivity pneumonitis).

Switching to 6MWD, researchers found improvement in this measure from baseline to week 16 among patients receiving mosliciguat (least-squares mean change, +20.3 m), whereas this measure fell among patients receiving placebo (least-squares mean change, –14.9 m). The difference between the two groups was 35.2 m (P = .0027).

By week 20, the difference in 6MWD between patients receiving mosliciguat and patients receiving placebo grew to 44.6 m (nominal P < .0001), and by week 24, it was 52.7 m (nominal P < .0001).

“These are patients who are continuing to improve against a backdrop of placebo patients who are continuing to deteriorate,” Gline said.

Similar to 6MWD, the mosliciguat group had more improvement in NT-proBNP between baseline and week 16 than the placebo group (placebo-adjusted change = –53.2%; P = .0002). The difference between the groups increased at week 20 (–66.2%; nominal P < .0001) and at week 24 (–75.9%; nominal P < .0001).

“The substantial improvements in 6-minute walk distance (+52.7 m at week 24) and NT-proBNP (–75.9%) were impressive,” Rali told Healio.

Researchers also examined change in mean pulmonary arterial pressure (mPAP) at week 16 and found more improvement among those receiving mosliciguat vs. placebo (median change, –9.17 mmHg vs. –0.5 mmHg; difference = –22.8%; nominal P < .0001).

Cardiac output was also more improved in the mosliciguat vs. placebo group (median change, 0.92 L/minute vs. –0.2 L/minute; difference = +26.2%; nominal P < .0001).

Time to clinical worsening, meaning “the first occurrence of one or more of: hospitalization for cardiopulmonary indication, decrease in 6MWD [greater than] 15% from baseline, lung transplantation for worsening PH, rescue therapy for PH [and] death (all causes),” was assessed as an exploratory endpoint.

Compared with patients receiving placebo, patients receiving mosliciguat had a 37% lower risk for this endpoint (HR = 0.63).

Additionally, a smaller proportion of the mosliciguat vs. placebo group had cough (12.1% vs. 18.2%), according to the webcast presentation.

“The lower cough rate compared with placebo was unexpected for an inhaled therapy and may represent a clinically meaningful advantage,” Rali told Healio.

Delving further into the safety of mosliciguat, a smaller proportion of patients receiving mosliciguat vs. placebo had any treatment-emergent adverse event (80.2% vs. 86.4%). The mosliciguat group had higher proportions of serious adverse events (33% vs. 27.3%) and treatment-emergent adverse events leading to discontinuation (12.1% vs. 4.5%). Three patients in the mosliciguat group and one patient in the placebo group died.

Headache was the most frequent treatment-emergent adverse event among those receiving mosliciguat (17.6% vs. placebo, 6.8%), followed by edema peripheral (14.3% vs. 11.4%), upper respiratory tract infection (14.3% vs. 2.3%), nausea (13.2% vs. 6.8%), cough, diarrhea (12.1% vs. 11.4%), dyspnea (11% vs. 13.6%) and vomiting (11% vs. 2.3%).

“[Phase 2] results were very encouraging for the advanced lung disease PH population,” Rali said.

Looking ahead, Gline said the global, multicenter, double-blinded phase 3 PHrontier study for mosliciguat in PH-ILD is underway. The target enrollment is 375 patients, and endpoints of 6MWD, time to clinical worsening, PVR and NT-proBNP will be assessed at 24 weeks.

Patients with background treprostinil use are permitted in this trial, according to the webcast.

“If confirmed in phase 3, [mosliciguat] could become the first non-treprostinil approved therapy for PH-ILD and offer a convenient once-daily inhaled option,” Rali told Healio. “The phase 3 study will have patients on background treprostinil therapy, so potentially opening up the options for dual inhaled therapy in this population.

“Larger phase 3 studies are needed to confirm efficacy, establish long-term safety, evaluate outcomes in patients receiving background treprostinil and determine whether the hemodynamic improvements translate into durable clinical benefit,” he said.

Parth M. Rali, MD, FCCP, can be reached at parth.rali@tuhs.temple.edu.