Firibastat: An Oral First-in-Class Brain Aminopeptidase A Inhibitor for Systemic Hypertension

Area of Science:

• Cardiovascular Research
• Neuropharmacology
• Hypertension Management

Background:

• Systemic hypertension is a major global health burden.
• Managing hypertension is complex, particularly in salt-sensitive individuals with low renin.
• The brain's renin-angiotensin system (RAS) significantly impacts blood pressure regulation.

Purpose of the Study:

• To investigate the role of brain RAS in hypertension.
• To evaluate EC33, an aminopeptidase A inhibitor, for its blood pressure-lowering effects.
• To develop a blood-brain barrier-penetrant prodrug (firibastat) for brain RAS inhibition.

Main Methods:

• Administration of EC33 in various rat hypertension models.
• Development of firibastat (RB150/QGC001) as a prodrug of EC33.
• Preclinical efficacy studies and Phase 2 clinical trials of firibastat.

Main Results:

• EC33 demonstrated significant blood pressure reduction in preclinical models.
• Firibastat showed efficacy and was well-tolerated in healthy participants and Phase 2 trials.
• Firibastat effectively crosses the blood-brain barrier.

Conclusions:

• Brain aminopeptidase A inhibition is a viable strategy for hypertension treatment.
• Firibastat is a promising therapeutic agent for resistant hypertension.
• Firibastat is advancing to Phase 3 trials based on its safety and efficacy profile.