Omapatrilat
Omapatrilat (Bristol-Myers Squibb’s Vanlev) is the leading compound in the VPI class. No development has been reported since July 2002, when the FDA advisory panel refused to recommend approval of omapatrilat for the treatment of hypertension — even as a last resort for patients with the most difficult-to-treat hypertension — and requested further trial data. This setback is just one of many for omapatrilat. Bristol-Myers Squibb filed the initial NDA in the United States in 1999 but withdrew it in 2000 out of concern about the incidence of angioedema (localized edema caused by dilation and increased permeability of the capillaries, a side effect of angiotensin-converting enzyme inhibition). The company applied for European approval in 1999 but withdrew its European marketing authorization application (MAA) after a European Medicines Agency assessment, possibly in reaction to its experience with the FDA.
Omapatrilat is a potent dual metalloprotease inhibitor, with activity against angiotensin-converting enzyme and NEP. Several clinical studies have highlighted its antihypertensive actions. One study showed that omapatrilat treatment (starting dose 10 mg for one week, raised to 40 mg for another three weeks) of 400 hypertensive patients reduced systolic blood pressure by 16 mm Hg, compared with 10 mm Hg for the angiotensin-converting enzyme inhibitor lisinopril (starting dose 10 mg for one week, raised to 20 mg for another three weeks). In a study of 657 patients with mild-to-severe hypertension, omapatrilat reduced diastolic blood pressure when combined with the commonly used diuretic hydrochlorothiazide. These patients did not respond to the diuretic alone. When omapatrilat was added, a significant number of patients (59% of the group receiving 10-20 mg omapatrilat and 64% of the group receiving 20-40 mg omapatrilat) showed normalized diastolic blood pressure. Only 38% of the placebo-treated group showed normalized blood pressure. These studies did not address the issue of angioedema.
The 25,000-patient Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) trial compared the efficacy of omapatrilat with that of the ACEI enalapril in the treatment of uncontrolled hypertension over a 24-week period. The trial was completed in October 2001 and the results disclosed in March 2002. More patients in the enalapril group needed an increase in dosage or an additional antihypertensive treatment to reach blood pressure targets.
Omapatrilat achieved greater systolic blood pressure reductions, on average 3 mm Hg, whether used alone or in combination with other antihypertensive agents. These reductions were seen across a broad range of patient groups, including those with severe hypertension, diabetes, or renal disease. There was also a 9% increase in the number of patients reaching the blood pressure goals of systolic blood pressure 140 mm Hg and diastolic blood pressure 90 mm Hg in the omapatrilat arm of the study compared with the enalapril arm.
Safety profiles for omapatrilat and enalapril in OCTAVE were similar, except for an increased risk of angioedema in the omapatrilat-treated group. The overall incidence of angioedema was 2.17% in the omapatrilat group and 0.68% in the enalapril group. Incidence was higher in black patients (5.54% with omapatrilat and 1.62% with enalapril) than in nonblack patients (1.78% with omapatrilat and 0.55% with enalapril). Also evident was a higher risk of angioedema in smokers. The most common manifestation of angioedema was face and lip swelling, although two cases of airway compromise were also reported in the omapatrilat group. Bristol-Myers Squibb reported that all angioedema patients fully recovered, but the overall incidence of this complication is clearly three times the incidence associated with the ACEI in this very large study population.
Following the publication of OCTAVE in July 2002, the FDA’s Cardiovascular and Renal Drugs Advisory Committee discussed the NDA and once again rejected it, even to treat patients with resistant hypertension. The committee cited the drug’s poor side-effect profile for the rejection.
Prior to initiating OCTAVE, Bristol-Myers Squibb conducted a retrospective analysis of its omapatrilat studies and identified a potential trend: incidence and severity of angioedema appeared to be associated with high starting doses of omapatrilat (20 mg or higher). Therefore, the OCTAVE trial used a lower, 10 mg starting dose. Certainly angioedema was not avoided in OCTAVE despite its use of a lower dose of the drug, a fact that supports the idea that the angioedema is idiopathic and makes the situation more perilous for Bristol-Myers Squibb.
In October 2002, the FDA issued an action letter stating that at least one additional clinical trial is needed before it would consider approval. The agency requested that the trial focus on the superior antihypertensive actions of omapatrilat in patients resistant to other medications used in combination at their highest possible doses. In view of the FDA’s letter, the scope for omapatrilat’s use for the treatment of hypertension appears to be shrinking. The drug is likely to be approved for only a very small number of hypertensive patients — those who are highly resistant to current therapies and whose care is managed primarily by a specialist rather than by a primary care physician (PCP)/general practitioner (GP).
Other confounding factors are the disappointing data released from large-scale clinical trials of omapatrilat in patients with heart failure. The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE), which involved 5,770 patients with moderate-to-severe heart failure, found that omapatrilat is only as effective as enalapril in reducing the primary end point: combined risk of death or hospitalization for heart failure requiring intravenous treatment. Interestingly, earlier studies were more promising. Bristol-Myers Squibb initiated the Omapatrilat in Persons with Enhanced Risk of Atherosclerotic Events (OPERA) trial to investigate whether omapatrilat could provide survival and clinical end point benefits in elderly patients (65 or older) with stage 1 isolated systolic hypertension over a five-year period. This trial appears to have been discontinued, adding to speculation that Bristol-Myers Squibb has abandoned omapatrilat.
This post has been viewed 691 times.
Comments are closed.
