The Rise and Fall of Omapatrilat

Thomas G. Pickering, MD, DPhil

Disclosures

Introduction

This column does not usually deal with antihypertensive drug issues, but I happened to be a participant in the recent review by the Food and Drug Administration (FDA) Cardiorenal Advisory Committee of the application for omapatrilat as an antihypertensive agent by Bristol-Myers Squibb (BMS), and it makes an interesting story. This was its second FDA review, and when it was first reviewed in March, 2000 it was hailed as the first of an entirely new class of antihypertensive agents, the vasopeptidase inhibitors. These agents are essentially "super ACE inhibitors," and have a dual action, combining inhibition of both the angiotensin-converting enzyme (ACE) and neutral endopeptidase. The latter enzyme is responsible for the breakdown of the three natriuretic peptides -- atrial natriuretic peptide, brain-derived natriuretic peptide, and C-type natriuretic peptide -- and bradykinin. The natriuretic peptides have actions that might be considered beneficial for hypertensive patients -- vasodilation, natriuresis, and inhibition of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Neutral endopeptidase inhibition was tested as a possible means of lowering blood pressure, but on its own was found to be ineffective.[1] However, numerous studies of omapatrilat (not all of which appear to have been published as full papers) have shown that it is a highly potent antihypertensive agent, and when compared with some of the leading antihypertensives such as losartan, amlodipine,[2] lisinopril,[3] and enalapril, it beat them all. Somewhat surprisingly, this extra potency cannot be attributed to a diuretic effect, which appears to be weak. Furthermore, when omapatrilat is added to a thiazide, there is an additional antihypertensive effect.[4] One factor that may give vasopeptidase the edge over ACE inhibitors as antihypertensives may be their greater potentiation of bradykinin,[5] but as we shall see below, this may also be their Achilles heel. These encouraging results in the treatment of hypertension were bolstered by equally exciting initial results in heart failure. The Inhibition of Metallo Protease by BMS-186716 in a Randomized Exercise and Symptoms Study in Subjects With Heart Failure (IMPRESS) trial[6] randomized patients with congestive heart failure to either omapatrilat (289 patients) or lisinopril (284). At the end of 7 months there were significantly fewer end points (hospitalizations for heart failure or mortality) in the omapatrilat group. In 2000, confident that they had a blockbuster antihypertensive in the wings, BMS took out one page nonpromotional advertisements in the national press titled "an open letter to healthcare providers nationwide," which pointed out that hypertension control in the United States was abysmal, and exhorting health care providers to make a commitment to improve the situation. It was signed by 35 hypertension experts (including Dr. Marvin Moser and myself and many members of the editorial board of this journal). No drugs were mentioned.

As a result of these findings, two large and more definitive outcome studies were planned. The first was OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events), which enrolled 5770 heart failure patients randomized to enalapril or omapatrilat. The results, which were announced at the American College of Cardiology in 2002,[7] were disappointing, since there was no effect on the major end points, which included death and hospitalization for heart failure. The second was OPERA (Omapatrilat in Persons With Enhanced Risk of Atherosclerotic Events).[8] This was an interesting design, since it proposed to study people with borderline isolated systolic hypertension (systolic pressures between 140-159 mm Hg), who were randomized to be treated either with omapatrilat or placebo. Such individuals are known to be at increased risk, but it is not known if treating them will lower it. The plan was to study 12,600 subjects, who would be followed for 5 years. The OPERA study has now been dropped.

The FDA reviewed the original application for omapatrilat in March of 2000. The safety database consisted of 9372 patients who had been treated with omapatrilat. No deaths were reported, but the most serious adverse event was angioedema, which occurred in 0.5% of patients, and was life threatening in four (requiring emergency intubation or cricothyrotomy/tracheostomy). At the FDA meeting it appeared that the occurrence of severe angioedema was higher than with any ACE inhibitors, and BMS was instructed to find a way around this problem, or the approval of omapatrilat would be at risk. In these studies, many of the patients had been started on the 20 mg dose, and it appeared that starting with the 10 mg dose might be associated with a lower incidence of angioedema.

OCTAVE[9] (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) was primarily designed to see if starting with a smaller dose of omapatrilat would result in a lower incidence of angioedema. The study design involved recruiting 25,000 patients with previously treated or untreated hypertension who were randomized to be treated with either enalapril (starting at 5 mg and increasing to 40 mg daily) or omapatrilat (10-80 mg). Patients with a history of angioedema, anaphylaxis, or multiple drug allergies were excluded. For the first 8 weeks only the study drugs could be used, but at 8 and 16 weeks additional medications could be added to try to get the patients to the goal blood pressure of 140/90 mm Hg. Throughout the 24-week study the blood pressure readings were lower (by about 3/2 mm Hg) in the omapatrilat group. The primary hypothesis was that by starting with the smaller dose of omapatrilat the incidence of angioedema would be no greater than twice the amount seen with enalapril, putting omapatrilat in the ballpark of the ACE inhibitors. However, the data failed to confirm this hypothesis, and showed a risk that was 3.2 times higher than that for enalapril. An independent committee that adjudicated the reported angioedema events concluded that there were 274 events in the omapatrilat group, and 86 in the enalapril group.

Apart from the larger numbers, there were two other important differences between the two groups. First, the time course was quite different, with many of the omapatrilat cases occurring soon after the first dose; thus, there were 91 cases reported on the first day of exposure to the study drugs, of which 88 were in the omapatrilat group. Second, the cases of angioedema seen with omapatrilat were more likely to be severe; the relative risk of all cases of angioedema was 3.1 times higher in the omapatrilat group, but the risk for angioedema requiring hospitalization was 9.5 times higher. It was also possible to identify risk factors predisposing to angioedema, foremost among which were black race (2.96 times higher for omapatrilat) and smoking (2.58 times higher). The higher risk in blacks was compounded by the fact that angioedema from ACE inhibitors is also more common in blacks than whites, so the absolute risk of angioedema from omapatrilat in OCTAVE was 5.54% in blacks, or more than 1 in 20 patients.

The issue confronting the committee was thus a classic question of balancing risks versus benefits. The sponsors of the application, BMS, recognized the increased risk, and proposed that the approval should be limited to patients at high risk for cardiovascular events, such as a previous history of cardiovascular disease, target organ damage, or diabetes, and hypertension that is difficult to control. The central argument of BMS was that an additional reduction of 3/2 mm Hg in these patients would lower the risk of events by 20-30 per 10,000 patient-years, and that would more than outweigh the 1.6 per 10,000 risk of serious angioedema. It sounds like a convincing argument, so why did the Committee not approve the drug? Central to the discussion was the validity of the assumption that the addition of omapatrilat would automatically lead to improved blood pressure control. Looking at the trends in blood pressure control over the last 20 years does not actually lend any support to this idea. We have witnessed the introduction of two completely new classes of antihypertensive drugs, the ACE inhibitors and the angiotensin receptor blockers, and the annual expenditure on antihypertensive drugs has increased dramatically, but there is not a shred of evidence that there has been any meaningful improvement in the rate of blood pressure control, which remains at 27%-29%.[10] In contrast to this dismal state of affairs, two recent studies, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)[11] and the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE),[12] both treating hypertensive patients who were at somewhat increased risk, have reported that simply following a predetermined protocol, and using conventional and readily available drugs, could increase the control rate to more than 65%. In addition, there was some concern that the design of OCTAVE, the results of which were the basis of the 3/2 mm Hg superiority claim for omapatrilat, did not really allow or encourage aggressive addition of other antihypertensives to get the patients to the goal blood pressure. In part, this was because there were only two visits at which additional drugs could be added. Thus, in the previously untreated group of patients, only 19% in the enalapril group and 13% in the omapatrilat group were given any additional drugs. Nevertheless, all of us who treat hypertensive patients have some refractory patients who remain stubbornly hypertensive whatever drugs we prescribe, and it would be good to have something new to offer them. But how effective omapatrilat would be at bringing this refractory group under control is a matter of speculation.

The issue of angioedema was also extensively discussed. Currently, ACE inhibitors are the most common cause, although there are rare hereditary cases. The symptoms, which include swelling of the eyelids, lips, face, tongue, and throat, usually develop over several hours, but in severe cases progress over 1-2 hours. It is generally accepted that these are due to venodilation that is mediated by bradykinin. Since vasopeptidase inhibitors increase bradykinin levels more than ACE inhibitors, this would explain the higher incidence of angioedema. However, it also suggests that angioedema with vasopeptidase inhibitors may be a class effect. BMS's proposed strategy to deal with angioedema, which clearly cannot be prevented at the present time, was to institute a comprehensive risk management program, which would include product labeling and patient counseling by pharmacists. There would also be a post-marketing surveillance program. This was met with some skepticism, on the grounds that there is scant evidence that brief educational programs do much to change patient behavior.

The final vote from the Committee was 5-1 against approval. Whether this will mean the end of omapatrilat is unclear, but as one BMS executive said to me at the end of the meeting: "It's tough being first." Certainly it is likely to put a damper on vasopeptidase inhibitors as a class and research on another medication in this class has just been suspended. Hopefully this event may spur more research on the causes and prevention of angioedema. How many of us routinely warn our patients about it when we start them on ACE inhibitors? Ironically, the first patient I saw after returning from the meeting, who happened to be black, was complaining of swelling of the face and lips; he was taking an ACE inhibitor.

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