Inhaled drug shows promise for rare lung disease combination

A therapeutic principle rooted in decades of pulmonary vascular research is entering a new stage of clinical development. The investigational inhaled drug mosliciguat, a soluble guanylate cyclase (sGC) activator, has produced marked and consistent effects in a randomized phase 2 study involving patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD), one of the most challenging forms of pulmonary vascular disease.

The development represents the latest chapter in a longstanding translational research program focused on the nitric oxide–sGC–cGMP pathway involving the Giessen lung research community. Earlier collaborative work between researchers in Giessen and pharmaceutical scientists working with Johannes-Peter Stasch at Bayer established pharmacological stimulation of sGC as a new therapeutic concept in pulmonary hypertension. This research ultimately contributed to the development of riociguat, the first sGC stimulator approved for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. The achievement was honored with the 2015 German Future Prize of the Federal President.

Mosliciguat extends this concept in an important new direction. Whereas sGC stimulators act predominantly on heme-containing sGC, sGC activators can target dysfunctional, nitric oxide-insensitive and heme-free forms of the enzyme that accumulate under conditions of oxidative stress. Such conditions are characteristic of chronically inflamed and remodeled lung tissue and pulmonary vessels.

Delivered directly to the lung as a dry-powder inhalation, mosliciguat is designed to restore cGMP signaling locally while limiting systemic vasodilator effects.

The first clinical proof of concept has now undergone peer review. In the recently published phase 1b ATMOS study in Thorax, patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension showed sustained reductions in pulmonary vascular resistance after a single inhaled dose of mosliciguat. Most adverse events were mild, and no safety-relevant changes in systemic vascular resistance or blood pressure were observed.

These findings paved the way for the international randomized, double-blind, placebo-controlled PHocus phase 2 study, which enrolled 135 adults with PH-ILD at 87 centers across 20 countries.

At week 16, the study met its primary endpoint with a 56.3% placebo-adjusted reduction in pulmonary vascular resistance. The treatment effect favored mosliciguat across all prespecified subgroup analyses, including different forms of underlying interstitial lung disease, degrees of pulmonary vascular disease, concomitant antifibrotic treatment and use or nonuse of PDE5 inhibitors.

The hemodynamic improvement was accompanied by a significant improvement in exercise capacity. Six-minute walking distance improved by 35.2 meters (115 feet) versus placebo at week 16 and, in the prespecified exploratory analysis, the placebo-adjusted difference increased further to 52.7 meters (173 feet) at week 24. Marked improvements were also observed in NT-proBNP and other measures of right-heart and pulmonary vascular function.

Werner Seeger said: “What is particularly important to us is the continuity of the scientific concept. The NO–sGC–cGMP pathway has been investigated in Giessen for decades, from fundamental vascular biology and experimental pharmacology through the first successful translation with riociguat. Mosliciguat now takes this principle into a biologically distinct disease setting and represents precisely the kind of long-term bench-to-bedside research that the Institute for Lung Health and the German Center for Lung Research were created to enable.”

The clinical translation has been driven in large part by Ardeschir Ghofrani, a senior pulmonary vascular researcher at the Giessen lung research hub, in collaboration with the pulmonary vascular research teams of the Institute for Lung Health (ILH), Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), international investigators and the sponsoring company Pulmovant, which is now responsible for the global clinical development program.

Ghofrani said: “PH-ILD remains a disease with a very high medical need. What is encouraging in PHocus is not only the magnitude of the pulmonary vascular effect, but its consistency across prespecified patient groups and the accompanying improvement in exercise capacity. These phase 2 results provide a strong rationale for phase 3. The decisive next step is now to confirm these findings in a larger population and determine whether they translate into sustained clinical benefit for patients.”

Friedrich Grimminger said, “This is not just another translational success of our lung research group here in Giessen. More importantly, it highlights the value of implementing top-notch scientific findings through regional, national and international hospital networks, like those we developed over the past three decades. Particularly in areas of high unmet medical need and rare diseases, the size and reach of such networks matter.”

Khodr Tello said, “In lung fibrosis patients, pulmonary vascular abnormalities also contribute to the development of PH, which then negatively affects the right ventricle, leading to myocardial remodeling and maladaptation, the main determinant of prognosis in these patients. An echocardiographic subgroup analysis examined this sequence in detail, thereby comprehensively characterizing the effects of this novel investigational drug.”

The global PHrontier phase 3 trial is already underway. Approximately 375 patients with PH-ILD are planned to be randomly assigned to receive mosliciguat or placebo. The primary endpoint is change in six-minute walking distance after 24 weeks; key secondary outcomes include time to clinical worsening, pulmonary vascular resistance and NT-proBNP.

The study marks another milestone in a translational research trajectory that began with understanding a fundamental physiological pathway and has already resulted in an approved treatment for pulmonary hypertension. Mosliciguat remains an investigational drug and has not been approved for the treatment of PH-ILD.

Provided by
Institute for Lung Health (ILH) and German Center for Lung Research (DZL)

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