Roivant Introduces Mosliciguat, a Novel Inhaled sGC Activator

Roivant has unveiled its previously undisclosed pipeline program for mosliciguat, a potential first-in-class, once-daily inhaled soluble Guanylate Cyclase (sGC) activator. This drug is designed for targeted delivery to the lungs via a dry powder inhaler (DPI) and is being developed to treat pulmonary hypertension associated with interstitial lung disease (PH-ILD), a condition affecting approximately 200,000 patients in the U.S. and Europe. PH-ILD has a higher prevalence than pulmonary arterial hypertension (PAH) but has limited to no treatment options.

The Phase 1b ATMOS study, presented at the European Respiratory Society (ERS) Congress, provided promising results. A single dose of inhaled mosliciguat in pulmonary hypertension (PH) patients resulted in sustained and clinically meaningful reductions in pulmonary vascular resistance (PVR) by up to 38%. These reductions are among the highest observed in PH trials to date. Additionally, the once-daily DPI dosing was generally well-tolerated with low rates of treatment-emergent adverse events (TEAEs).

Mosliciguat has undergone extensive characterization in a robust Phase 1 program, including 170 participants, and has shown potential differentiation in terms of efficacy, safety, and convenience. The drug targets sGC, a crucial enzyme in the nitric oxide (NO) / cyclic guanosine monophosphate (cGMP) signaling pathway. This pathway is responsible for catalyzing cGMP production, leading to increased vasodilation, reduced inflammation, apoptosis inhibition, reverse vascular remodeling, and anti-fibrotic effects.

Unlike sGC stimulators, which require reduced heme and NO to be effective, mosliciguat is an sGC activator that operates independently of these components. This mechanism allows mosliciguat to potentially maintain efficacy in highly oxidative environments typical of PH, where stimulators might lose efficacy due to oxidized or removed heme and depleted NO levels.

The ATMOS trial was a non-randomized, open-label, dose-escalation, proof-of-concept Phase 1b study assessing the efficacy, safety, tolerability, and pharmacokinetics of mosliciguat after single-dose inhaled administration. Participants ranged from 18 to 80 years old and included those with World Health Organization (WHO) Group 1 PH (PAH) or Group 4 PH (chronic thromboembolic pulmonary hypertension (CTEPH)). In this study, 38 patients received mosliciguat, and the results showed mean-max peak reductions in PVR from baseline of -25.9%, -38.1%, and -36.3% for the 1.0, 2.0, and 4.0 mg doses, respectively, surpassing the predefined threshold for the primary outcome.

The data also indicated that mosliciguat's novel mechanism of action might allow for broad activity across the PH spectrum, including participants both responsive and non-responsive to inhaled NO. This was presented during the ERS Congress in Vienna.

Overall, in its Phase 1 development program involving 170 healthy volunteers and PH patients, mosliciguat demonstrated a favorable safety profile, dose-dependent increases in cGMP, and a 40-hour half-life supporting convenient dosing. Mosliciguat stands out among inhaled PH therapies as it requires just one puff once per day, unlike currently approved therapies that necessitate multiple puffs several times a day. The DPI formulation provides greater convenience and minimizes the risk of serious adverse effects associated with systemic vasodilators, like worsening oxygenation status.

Mosliciguat's superior efficacy, safety, and ease of administration support its potential differentiation. Pulmovant, a wholly-owned Roivant subsidiary, will advance the clinical program to the global Phase 2 PHocus study, which will enroll approximately 120 patients with PH-ILD. This study aims to address a significant unmet need, given the high PH-ILD prevalence and limited treatment options, offering an attractive commercial opportunity with minimal competition.

Roivant licensed mosliciguat from Bayer, with the latter receiving an upfront payment of around $14 million and up to an additional $280 million for future milestones, along with tiered high-single digit sales-based royalties. Roivant's portfolio continues to expand with innovative therapies aimed at improving patient outcomes.