FRESH –First-in-Class Aminopeptidase-A Inhibitor Firibastat Fails in Resistant Hypertension

By Gabriel Pajares-Hurtado on

Key Points

  • Hypertension remains a major public health threat contributing significantly to rates of ischemic heart disease and strokes worldwide despite a wide array of antihypertensives available
  • A new antihypertensive agent, firibastat, is a first-in-class prodrug that acts through the inhibition of amiopeptidase A to block the conversion of angiotensin II to angiotensin III resulting in a decrease in blood pressure
  • Firibastat failed to demonstrate efficacy to decrease blood pressure in patients with difficult-to-treat/resistant hypertension and was associated with allergic skin reactions.

Despite the wide array of antihypertensive agents available to target lower blood pressures, hypertension remains a major public health threat contributing significantly to rates of ischemic heart disease and strokes worldwide. In patients for which traditional therapies do not control their blood pressure, newer agents offer hope for treatment of their pressures. The results of a trial evaluating a new, first-in-class medication, firibastat, was presented by Dr. George Bakris (University of Chicago, Chicago, IL) at AHA 2022 conference this afternoon. Firibastat crosses the blood-brain barrier to inhibit aminopeptidase A, an enzyme responsible for converting angiotensin II to angiotensin III; given angiotensinogen III’s proposed three-prong mechanism to increase blood pressures, inhibition of amiopeptidase A results in blood pressure lowering effects. The “Top-Line Results of The First-in-Class Aminopeptidase-A Inhibitor Firibastat in Treatment-Resistant Hypertension Study,” or the FRESH study, brings forth long-awaited data regarding this new medication.


The FRESH study was a double-blind, placebo-controlled, multicenter, efficacy and safety study of firibastat 500 mg administered twice daily over 12 weeks to evaluate its effect on blood pressure in patients with uncontrolled primary hypertension. Inclusion criteria included uncontrolled primary HTN (SBP 140-180 mmHg at screening) despite being treated with 2 classes of antihypertensive drugs ( difficult-to-treat) or at least 3 classes including a diuretic (resistant), with medication adherence >80% during the run-in period, mean systolic daytime ABP >135 mmHg after the run-in period while on their current chronic antihypertensive treatments.


A total of 515 patients were randomized, with X receiving firibastat and the rest a matching placebo. The trial included a balanced distribution of patient characteristics across both groups with regard to age (mean 64), female sex (41.6%), and black patients (mean 13.6%), including a fair number of obese patients (mean 61.5%). Mean blood pressures in both groups were similar with a means of 146.63/84.30 and 145.68/83.99 in the treatment arm and placebo arm, respectively.


The primary outcome was systolic blood pressure measured in the office from day 1 to day 84 and the trial showed no significant reduction blood pressure with firibastat 500 mg twice daily compared to placebo (adjusted difference of +0.03 mmHg p = 0.98). Diastolic blood pressures and mean 24-hour ambulatory blood pressures were also measured as secondary outcomes; these, too, did not show significant reduction in either outcome. Of note, the medication was overall well tolerated, noting no serious related adverse events and no change in liver enzymes, eGFR, or serum potassium levels. There were allergic skin reactions associated with the medication limited to exanthema, skin rashes, and pruritus; none were reported as a serious adverse event.


Despite having a well-constructed trial design, Dr. Bakris noted that the FRESH trial was ultimately a “negative study”, with antihypertensive drug hopeful, firibastat, failing to demonstrate efficacy to decrease unattended office systolic blood pressure in patients with difficult-to-treat and resistant hypertension. The results of the trial were consistent across all subgroups and secondary endpoints.