Omapatrilat belongs to the
vasopeptidase inhibitors, ie, drugs that possess the ability to inhibit simultaneously the membrane-bound
zinc metalloproteases,
angiotensin-converting enzyme (ACE), and the
neutral endopeptidase EC 3.4.24.11 (NEP).
Omapatrilat was targeted to treat patients with
hypertension and
congestive heart failure. The preclinical and early clinical studies conducted with
omapatrilat were very promising. Indeed,
omapatrilat appeared to be a very potent
antihypertensive agent with very favorable effects on cardiac function in
heart failure patients. In contrast to these early studies, the large clinical trials were more disappointing. The results of the OCTAVE trial confirmed the
antihypertensive efficacy of
omapatrilat, but at the price of an
angioedema rate more than threefold higher than that of an
ACE inhibitor in the overall population (2.17% vs 0.68%), and close to fourfold higher in the black population. In OVERTURE, a large randomized control trial in
heart failure,
angioedema was also more common with
omapatrilat, but the incidence was much lower (0.8% with
omapatrilat vs 0.5% with
enalapril). However,
omapatrilat was not convincingly superior to the
ACE inhibitor. Because
angioedema is probably a class side effect of
vasopeptidase inhibitors, the higher incidence of this potentially life-threatening complication with
omapatrilat has likely stopped the development of this new class of agents. The future of
vasopeptidase inhibitors will depend on the ability to improve the risk/benefit ratio either by developing agents that produce less
angioedema, or by defining more precisely a high-risk population that could take advantage of dual ACE/NEP inhibition.