Phase 2 PHocus results and trial milestones
- Roivant Sciences and its subsidiary Pulmovant reported that the Phase 2 PHocus trial evaluating inhaled mosliciguat met its primary and secondary endpoints in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD).
- Patients receiving mosliciguat achieved a 56.3% placebo-adjusted reduction in pulmonary vascular resistance (PVR) at Week 16 (p<0.0001), driven by a 51.3% drop in the treatment group compared with a 6.6% increase in the placebo group.
- Exercise capacity improved by a placebo-adjusted 35.2 meters in the six-minute walk distance (6MWD) test at Week 16 (p=0.0027), expanding to 52.7 meters at Week 24 in exploratory follow-up.
- Cardiac strain measured by the biomarker NT-proBNP fell by a placebo-adjusted 357.7 pg/mL (53.2% reduction from baseline) at Week 16 (p=0.0002) and by 487.1 pg/mL (75.9%) at Week 24.
- Patient enrollment has commenced for the global Phase 3 PHrontier trial, designed to evaluate approximately 375 adult patients worldwide.
| Finding | Plain-English meaning |
|---|---|
| 56.3% placebo-adjusted reduction in PVR at Week 16 (p<0.0001) | The experimental medicine significantly lowered blood vessel resistance inside the lungs compared to dummy treatment. |
| 35.2-meter placebo-adjusted gain in 6-minute walk distance at Week 16 | Patients taking the once-daily inhaled drug walked farther in six minutes than those on placebo, who showed a 14.9-meter decline. |
| 53.2% placebo-adjusted drop in NT-proBNP cardiac biomarker | Blood levels of a key protein that signals heart strain decreased substantially after 16 weeks of treatment. |
| 12.1% cough incidence with mosliciguat versus 18.2% with placebo | The inhaled drug was well tolerated and caused lower rates of coughing than the inactive dummy spray during the trial. |
Understanding PH-ILD and the soluble guanylate cyclase target
Pulmonary hypertension associated with interstitial lung disease, known as PH-ILD, falls under Group 3 pulmonary hypertension. Interstitial lung disease encompasses a broad spectrum of conditions that inflict progressive damage on lung tissue, causing persistent stiffness and shortness of breath. When pulmonary hypertension develops alongside it, blood pressure rises within the blood vessels of the lungs. This double strain forces the right ventricle of the heart to pump against higher resistance, worsening exhaustion and accelerating disease progression.
Mosliciguat is an experimental, once-daily inhaled medication developed as a soluble guanylate cyclase (sGC) activator. The sGC enzyme functions as a critical junction in the nitric oxide and cyclic guanosine monophosphate (cGMP) signaling pathway, catalyzing the production of cGMP. Elevated cGMP signals the smooth muscle lining pulmonary blood vessels to relax, reducing vascular resistance. Beyond vasodilation, cGMP signaling can reduce inflammation, limit tissue scarring (fibrosis), slow programmed cell death (apoptosis), and reverse structural vessel remodeling.
Think of pulmonary blood vessels like narrow pipes where pressure builds up; increasing cGMP acts like opening a pressure release valve to let blood flow more freely.
Mosliciguat differs mechanically from sGC stimulators. Standard sGC stimulators require nitric oxide and a non-oxidized heme group on the enzyme to function effectively. Mosliciguat activates sGC independently of nitric oxide levels and heme oxidation status. Oxidative stress in damaged lung tissue often impairs normal sGC enzymes. Activating oxidized sGC provides a targeted way to maintain signaling in diseased tissue. A prior clinical trial testing the sGC stimulator riociguat in Group 3 pulmonary hypertension was stopped early due to serious harm, highlighting the functional gap between sGC stimulators and sGC activators in this disease setting.
Comparative measurement data across PH-ILD clinical trials
| Trial metric | Phase 2 PHocus (Mosliciguat) | INCREASE trial (Inhaled Treprostinil) |
|---|---|---|
| Study design and size | Randomized 135 patients across 87 sites in 20 countries | Randomized 326 patients (163 drug / 163 placebo) |
| Primary endpoint duration | 16 weeks | 16 weeks |
| Primary outcome measurement | 56.3% placebo-adjusted PVR reduction (p<0.0001) | 31.12-meter 6MWD mean difference (p<0.001) |
| 6MWD placebo-adjusted change at Week 16 | 35.2 meters improvement (p=0.0027) | 31.12 meters improvement (p<0.001) |
| NT-proBNP relative change at Week 16 | 53.2% reduction from baseline (p=0.0002) | 15% reduction vs 46% placebo increase (p<0.0001) |
| Reported cough incidence | 12.1% in treatment group vs 18.2% in placebo group | Listed among most frequent adverse events |
In the Phase 2 PHocus trial, the primary endpoint focused on hemodynamic changes measured by right heart catheterization. Patients in the mosliciguat group demonstrated a 51.3% drop in PVR at Week 16, while patients in the placebo group experienced a 6.6% increase, generating the net 56.3% placebo-adjusted reduction. Roivant Sciences noted that this represents the largest PVR reduction recorded in a randomized controlled trial for pulmonary hypertension.
Functional capacity and cardiac biomarkers paralleled the hemodynamic improvements. In the six-minute walk test, patients treated with mosliciguat gained 20.3 meters at Week 16, whereas placebo recipients experienced a 14.9-meter decline, establishing a 35.2-meter net improvement (p=0.0027). The cardiac biomarker NT-proBNP decreased by 357.7 pg/mL in the mosliciguat group compared to placebo, representing a 53.2% baseline-adjusted drop (p=0.0002).
Pre-specified exploratory analyses indicated that treatment responses deepened through Week 24. At Week 24, the placebo-adjusted walk distance improvement reached 52.7 meters (nominal p<0.0001). The placebo-adjusted NT-proBNP reduction grew to 487.1 pg/mL, reflecting a 75.9% drop from baseline (nominal p<0.0001). By comparison, the 16-week INCREASE trial evaluating inhaled treprostinil (Tyvaso) recorded a 31.12-meter least-squares mean difference in walk distance and a 15% drop in NT-proBNP against a 46% increase in the placebo arm.
Clinical impact and disease context for lung patients
An estimated 200,000 individuals across the United States and Europe live with PH-ILD. Patient outcomes remain severe, with median survival ranging between 1.5 and 2 years despite available standard care.
Current medical management for PH-ILD remains sparse. Treatment options center primarily on inhaled treprostinil and off-label prescription of phosphodiesterase-5 (PDE5) inhibitors. Inhaled treprostinil requires ultrasonic nebulizer administration up to 12 breaths (72 ug) four times daily, with an initial target dose of 9 breaths four times daily. Frequent daily dosing schedules and airway irritation create compliance challenges.
Mosliciguat is formulated for once-daily inhalation. In the PHocus study, cough occurred in 12.1% of mosliciguat recipients compared to 18.2% of placebo recipients. Tolerability regarding cough is a critical consideration for inhaled medications in lung disease, as frequent coughing can compel patients to stop therapy. Marc Humbert, MD, PhD, Director of the French National Reference Center for Pulmonary Hypertension, described the PVR drop in PHocus as remarkable, noting the consistency across functional, hemodynamic, and cardiac marker endpoints.
Trial boundaries and nuances in the preliminary data
While the Phase 2 PHocus results demonstrate clear hemodynamic shifts, several context boundaries apply. The PHocus study evaluated 135 adult patients across 87 sites in 20 countries. While sufficient to meet primary hemodynamic endpoints, this sample size is smaller than Phase 3 registration studies.
The 24-week walk distance gain of 52.7 meters and the 75.9% NT-proBNP drop were derived from pre-specified exploratory analyses rather than primary study endpoints. Long-term hard clinical outcomes, such as mortality and time to clinical worsening, require further evaluation in larger patient groups over extended periods.
By contrast, the INCREASE trial enrolled 326 patients and tracked clinical worsening, which occurred in 22.7% (37 patients) of the inhaled treprostinil group compared to 33.1% (54 patients) of the placebo group (hazard ratio 0.61; 95% CI, 0.40 to 0.92; p=0.04). During the 16-week randomized phase of INCREASE, 10 deaths occurred in the treprostinil arm and 12 deaths in the placebo arm.
Next milestones and the Phase 3 PHrontier trial
Following the Phase 2 findings, Roivant Sciences and Pulmovant initiated the Phase 3 PHrontier trial, with patient enrollment now active.
PHrontier is structured as 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 designed to enroll approximately 375 patients worldwide. Drew Fromkin, Chief Executive Officer of Pulmovant, stated that the trial aims to evaluate whether once-daily inhaled mosliciguat can address existing treatment gaps as a monotherapy or combination therapy. Mayukh Sukhatme, President and Chief Investment Officer at Roivant, noted that chronic dosing in PHocus confirmed hypotheses generated during early ATMOS study evaluations. Roivant’s clinical pipeline also includes LISRAYA (brepocitinib) and IMVT-1402.
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Sources:
- Pulse 2.0, “Roivant Reports 56.3% Placebo-Adjusted PVR Reduction In Phase 2 Mosliciguat PH-ILD Study, Starts Phase 3 PHrontier Trial” (https://pulse2.com/roivant-reports-56-3-placebo-adjusted-pvr-reduction-in-phase-2-mosliciguat-ph-ild-study-starts-phase-3-phrontier-trial/)
- Thorax, “Survival analysis from the INCREASE study in PH-ILD: evaluating the impact of treatment crossover on overall mortality” (https://pmc.ncbi.nlm.nih.gov/articles/PMC10958253/)
- The New England Journal of Medicine, “Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease” (https://www.nejm.org/doi/full/10.1056/NEJMoa2008470)
Disclaimer: This article is for general information only and does not constitute medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider about any medical condition or before making health decisions.