Mosliciguat, a potential first-in-class inhaled medication, significantly reduced pulmonary vascular resistance in adults with pulmonary hypertension associated with interstitial lung disease (PH-ILD) in a phase 2 study presented at the European Respiratory Society (ERS) 2026 International Congress.

The promising findings support the initiation of a phase 3 trial, the PHrontier study, now open and enrolling patients, according to lead author Marc Humbert, MD, PhD, professor of pneumology at the Université Paris-Saclay in Gif-sur-Yvette, France.

PH-ILD remains the challenging form to treat, as few approved therapies have been studied in this population, said Humbert.

“Mosliciguat is distinct from sGC [soluble guanylyl cyclase] stimulators used in other forms of pulmonary hypertension, and it was designed specifically to deliver pulmonary vasodilation locally while limiting systemic exposure,” Humbert said.

In the phase 2 study, known as PHocus, 135 adult patients aged 18-85 years with interstitial lung disease were enrolled and randomized to 24 weeks of daily mosliciguat or placebo via dry powder inhaler. The primary outcome was the change in pulmonary vascular resistance from baseline to 16 weeks.

Mosliciguat targets sGC to promote blood flow and binds directly to the enzyme in a distinct mechanism of action independent of nitric oxide, according to a press release from manufacturer Roivant.

After 16 weeks, patients in the mosliciguat group had a significantly greater reduction in pulmonary vascular resistance than those in the placebo group (-51.3% vs +6.6%; P < .0001).

The study also met secondary endpoints including a significantly greater improvement in the 6-minute walk test from baseline to 16 weeks in mosliciguat patients than in placebo patients (+20.3 m vs -14.9 m; P = .0027) and a clinically meaningful and significant placebo-adjusted reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP), an established biomarker for cardiac strain, of -53.2% from baseline. The effects favoring mosliciguat for the secondary endpoints were similar at week 24.

The drug was well tolerated overall, and fewer patients in the mosliciguat group reported cough than those in the placebo group (12.1% vs 18.2%).

“The magnitude of the hemodynamic effect was genuinely striking,” said Humbert.

What I found most encouraging, rather than surprising in a cautionary sense, was that the benefit appeared to be durable and in fact grew between week 16 and week 24 rather than plateauing or reversing,” Humbert said. “In a population where clinicians are often worried about a treatment doing more harm than good to the lungs, seeing this kind of consistent improvement across hemodynamic, functional, and biomarker endpoints together is not something we take for granted,” he added.

The results demonstrate that an inhaled sGC activator could improve pulmonary hemodynamics and exercise capacity in these patients left behind by other therapies, without the systemic and oxygenation-related tradeoffs, Humbert said. “Given this well tolerated safety profile, we are also allowing mosliciguat on top of inhaled treprostinil in the PHactor phase 2 and PHrontier phase 3 studies. For patients and their physicians, that would mean a therapy that addresses the underlying pulmonary vascular component of their disease rather than only managing symptoms,” he added. The PHrontier phase 3 study in PH-ILD is ongoing and enrolling.

Filling a Treatment Gap

Currently, inhaled treprostinil is the only approved therapy for patients with PH-ILD, said Parth M. Rali, MD, FCCP, professor of thoracic medicine and surgery at the Lewis Katz School of Medicine at Temple University in Philadelphia, who was not involved in the current study.

Inhaled treprostinil in its current form must be taken four times a day and often incurs cough as a side effect, noted Rali. The current phase 2 study evaluated whether once-daily inhaled mosliciguat could provide meaningful improvements in pulmonary vascular disease, exercise capacity, and cardiac function while maintaining good tolerability, he said.

Rali said that he expected a favorable response in the PHocus study based on phase 1 data presented at a previous ERS Congress. “However, the results were definitely very encouraging for the advanced lung disease PH population,” he said. “The magnitude of the pulmonary vascular resistance reduction was particularly notable, with a 56.3% placebo-adjusted reduction at week 16,” he said. The substantial improvements in 6-minute walk distance and NT-proBNP were also impressive, and the lower cough rate than placebo was unexpected for an inhaled therapy and may represent a clinically meaningful advantage, Rali said.

“Mosliciguat demonstrated improvements across multiple clinically relevant domains, including hemodynamics, exercise capacity, and biomarkers of right ventricular strain; if the results are confirmed in a phase 3 study, it could become the first non-treprostinil approved therapy for PH-ILD and offer a convenient once-daily inhaled option,” said Rali. “The phase 3 study will have patients on background treprostinil therapy, potentially opening up the options for dual inhaled therapy in this moribund population,” he added.

The PHocus study was limited in part by the relatively small number of patients and was not powered to definitively assess long-term clinical outcomes such as mortality or hospitalization, and the favorable trend of 37% reduction in time to clinical worsening did not reach statistical significance, Rali noted. “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.

The study was funded by Roivant. Rali had no financial conflicts to disclose.