• FP-045, a selective oral ALDH2 activator, has demonstrated good tolerance and a favorable safety profile in Phase I studies. The upcoming WINDWARD Phase II trial, set to commence in 2024, aims to evaluate its efficacy in PH-ILD patients, with interim results expected in 2025 and full results in 2026.
• ALDH2 (Aldehyde Dehydrogenase 2) is crucial for mitochondrial health and the regulation of oxidative stress and fibrosis. Activating ALDH2 presents a promising therapeutic approach for treating rare and severe diseases, including pulmonary hypertension associated with interstitial lung disease (PH-ILD).

Foresee Pharmaceuticals presented compelling new data on FP-045, an aldehyde dehydrogenase 2 (ALDH2) activator, at the 2024 American Thoracic Society (ATS) International Conference. The poster presentation underscored the company’s collaborative efforts with clinical experts in pulmonary hypertension and interstitial lung disease in designing the WINDWARD Phase II study. 

The study, detailed in Poster P1360, was featured in the “Bench to Bedside in ILD” session. The poster titled “A Multinational Phase II, Randomized, Double-blinded, Placebo-controlled, Multiple-dose Study to Evaluate the Safety and Efficacy of FP-045, An Aldehyde Dehydrogenase 2 Activator in Patients with Pulmonary Hypertension Associated with Interstitial Lung Disease,” showcases the meticulous design and promising potential of the WINDWARD Phase II study. This research is a testament to Foresee’s collaborative approach with clinical experts in addressing the critical needs of PH-ILD patients. It emphasized the innovative approach of Foresee Pharmaceuticals in targeting mitochondrial dysfunction in PH-ILD. 

FP-045 aims to mitigate pulmonary artery wall thickening by activating ALDH2, thereby reducing the accumulation of harmful aldehyde byproducts such as 4-hydroxynonenal (4-HNE).

Aldehyde Dehydrogenase 2 (ALDH2) is a crucial enzyme involved in detoxifying aldehyde byproducts of lipid peroxidation, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). These byproducts can accumulate due to oxidative stress and contribute significantly to disease progression in pulmonary hypertension by promoting pulmonary arterial smooth muscle cell proliferation. Foresee’s preclinical studies have demonstrated that ALDH2 activators, like FP-045, can effectively reduce pulmonary artery wall thickness in rodent models of PH, providing a strong rationale for exploring this therapeutic pathway in humans.

The WINDWARD Phase II trial, which is set to be initiated in 2024, is a 16-week, randomized, double-blind, placebo-controlled trial designed to evaluate the safety, tolerability, and efficacy of FP-045 in patients aged 18–85 with confirmed interstitial lung disease and pulmonary hypertension, characterized by elevated pulmonary vascular resistance (PVR) and specific hemodynamic criteria measured via right heart catheterization. Participants were randomized to receive either 150 mg or 300 mg of FP-045 or a placebo daily for 12 weeks. The primary endpoint was the mean change in PVR from baseline to Week 12, while secondary endpoints included changes in N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels, 6-min walk distance, and time to clinical worsening.

FP-045 has shown a favorable safety profile in prior studies, demonstrating good tolerance in healthy volunteers at single doses up to 750 mg IV and 1,200 mg PO (per os). Additionally, it exhibited no significant drug-related safety findings in Phase I multiple ascending dose (MAD) studies. The drug’s linear pharmacokinetics and absence of significant genotoxicity or toxicity in 28-day and 3-month GLP toxicology studies further underscore its potential as a viable therapeutic option.

Initial data indicate that FP-045 has a promising safety profile, having been well-tolerated in Phase I studies with no significant adverse events. The WINDWARD study is set to provide more comprehensive insights, with interim analysis in 2025 and full results expected in 2026. If successful, FP-045 could become a first-in-class therapy for PH-ILD patients, addressing a significant unmet medical need. The company is confident that the readout from this study will guide future development and regulatory approval efforts for FP-045 in this critically underserved patient population. 

 

Foresee Pharmaceuticals is committed to leveraging its innovative chemical entities to build a broad first/best-in-class franchise. The data presented at the ATS conference underscores the potential of FP-045 as a novel treatment for PH-ILD, marking a significant step forward in the fight against this challenging condition. As the WINDWARD Phase II study progresses, the medical community eagerly anticipates further insights into the efficacy and safety of FP-045, which could ultimately transform the therapeutic landscape for patients with PH-ILD, offering new hope for improved management and outcomes.