Roivant Sciences announced positive results from the Phase 2 PHocus study of mosliciguat in patients with pulmonary hypertension associated with interstitial lung disease, or PH-ILD, with the study meeting its primary and secondary endpoints and supporting advancement of the therapy into Phase 3 development.
The study’s primary endpoint showed a 56.3% placebo-adjusted reduction in pulmonary vascular resistance, or PVR, at Week 16, with a 51.3% reduction among patients receiving mosliciguat compared with a 6.6% increase for placebo. The result was statistically significant with p<0.0001.
Roivant said the result represents the largest PVR reduction reported in a randomized controlled pulmonary hypertension trial.
PHocus also met its secondary endpoints at Week 16.
Patients receiving mosliciguat demonstrated a 35.2-meter placebo-adjusted improvement in six-minute walk distance, or 6MWD, with the mosliciguat group improving by 20.3 meters compared with a 14.9-meter decline in the placebo group. The result was statistically significant with p=0.0027.
The study also showed a 357.7 pg/mL placebo-adjusted reduction in NT-proBNP, a biomarker of cardiac strain, corresponding to a 53.2% reduction from baseline at Week 16. That result was statistically significant with p=0.0002.
Pre-specified exploratory analyses indicated that treatment effects continued to strengthen through the end of the placebo-controlled period.
At Week 24, the placebo-adjusted improvement in six-minute walk distance increased to 52.7 meters, with a nominal p-value below 0.0001.
NT-proBNP showed a 487.1 pg/mL placebo-adjusted reduction at Week 24, representing a 75.9% reduction, also with a nominal p-value below 0.0001.
Mosliciguat was observed to be well tolerated, with Roivant reporting a favorable safety profile and adverse events consistent with the underlying PH-ILD condition.
The incidence of cough was 12.1% among patients receiving mosliciguat compared with 18.2% for placebo. Roivant highlighted the finding because cough can be a tolerability challenge associated with inhaled prostacyclins.
Mosliciguat is being developed as a potential first-in-class, once-daily inhaled soluble guanylate cyclase, or sGC, activator designed to provide targeted pulmonary vasodilation while limiting systemic side effects.
The drug targets sGC, a key enzyme in the nitric oxide and cyclic guanosine monophosphate signaling pathway that catalyzes cGMP production.
Elevated cGMP levels are known to promote vasodilation and may also contribute to anti-fibrotic effects, reduced inflammation and apoptosis, and reversal of vascular remodeling.
Unlike sGC stimulators, mosliciguat is designed to activate sGC independently of nitric oxide and heme status.
Roivant believes that mechanism could be particularly relevant in oxidative-stress-associated diseases such as PH-ILD, where normal sGC function may be impaired.
PH-ILD is a form of Group 3 pulmonary hypertension associated with interstitial lung disease.
Interstitial lung disease describes a broad group of conditions that cause progressive damage to the lungs, making breathing increasingly difficult. Pulmonary hypertension adds elevated blood pressure in the blood vessels of the lungs, forcing the heart to work harder to circulate blood.
Roivant estimates that up to 200,000 patients across the U.S. and Europe are living with PH-ILD and have limited or no approved treatment options.
The Phase 2 PHocus trial was a randomized, double-blind, placebo-controlled global study that enrolled 135 adult patients across 87 sites in 20 countries.
Following the Phase 2 results, Roivant has initiated the Phase 3 PHrontier study, with enrollment now underway.
PHrontier is a randomized 1:1, double-blind, placebo-controlled global trial evaluating the safety and efficacy of mosliciguat in adults with PH-ILD. The study is currently designed to enroll approximately 375 patients worldwide.
The transition into Phase 3 development reflects Roivant’s effort to move mosliciguat toward a potential treatment option for a patient population with substantial unmet need.
Roivant is developing mosliciguat through Pulmovant, one of its subsidiaries focused on pulmonary disease.
The company believes the combination of the Phase 2 efficacy results, once-daily inhaled administration and differentiated sGC activator mechanism could position mosliciguat as both a potential standalone treatment and combination therapy for PH-ILD.
Roivant’s broader pipeline also includes LISRAYA, or brepocitinib, and IMVT-1402, alongside mosliciguat.
KEY QUOTES:
“PH-ILD remains one of the most challenging forms of pulmonary hypertension to treat, given the heterogeneity of the disease and the fact that existing therapies are approved in limited geographies and poorly tolerated in patients with underlying lung disease. The PVR reduction observed in PHocus is remarkable and among the largest reported in a randomized controlled PH trial to date. The consistency of benefit across hemodynamic, functional, and cardiac biomarker endpoints makes these results even more impressive. Together, these results represent a clinically meaningful advancement in this field and highlight the potential of mosliciguat to address a longstanding gap in care for a patient population with high mortality and limited treatment options.”
Marc Humbert, MD, PhD, Professor of Respiratory Medicine at Université Paris-Saclay and Director of the French National Reference Center for Pulmonary Hypertension
“PH-ILD is a disease as bad as some forms of cancer, with a median survival of just 1.5-2 years despite best-available standard of care. We wanted to see if we could make an impact in this terrible disease when we brought mosliciguat into Roivant. Our thesis was that the ATMOS study actually understated the potential of mosliciguat – and when dosed chronically, it would do considerably more. These PHocus results proved that out as clearly as we could have hoped: a profound 56.3% placebo-adjusted PVR reduction – the largest PVR reported in any controlled pulmonary hypertension trial of any group. This data set puts mosliciguat in a league of its own on PVR reduction, 6MWD improvement, NT-proBNP % reduction, cough rate, and ease of use. It is a terrific example of the Roivant model working as planned: finding high-potential molecules and going after diseases where the patient needs are enormous and where the drug can truly shine.”
Mayukh Sukhatme, President and Chief Investment Officer at Roivant
“Our robust Phase 2 PHocus study results, in conjunction with mosliciguat’s inhaled, once-a-day administration and potential first-in-class sGC activator profile, strongly position it as a potential single agent treatment and combination therapy for patients with PH-ILD. Today, the treatment landscape is sparse, primarily consisting of formulations of inhaled treprostinil and their associated limitations, and off-label use of PDE5 inhibitors. With these results, mosliciguat has demonstrated that it may address many of these treatment gaps. We are truly grateful to the patients, investigators, and site teams who made this study possible. We are also pleased to announce that our Phase 3 PHrontier study for patients with PH-ILD has been initiated with the goal of rapidly bringing mosliciguat to patients battling PH-ILD.”
Drew Fromkin, Chief Executive Officer of Pulmovant
