Questions
omapatrilat
19 July 2002
The Committee is asked to opine on the approvability of omapatrilat for hypertension. Omapatrilat is an inhibitor of angiotensin converting enzyme and neutral endopeptidase. Reviews of chemistry, pharmacology, toxicology, and biopharmaceutics present no apparent barriers to approval. Omaparilat clearly lowers blood pressure. During its initial development, an increased risk of life-threatening angioedema was noted for patients taking omapatrilat compared with other antihypertensives (including ACE inhibitors). To characterize this safety finding and to gain additional information on the relative antihypertensive efficacy of omapatrilat, the sponsor conducted the OCTAVE trial.
OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) was a randomized, double-blind study in which 25302 subjects with hypertension were randomized to once-daily enalapril or omaparilat and followed for 24 weeks. During the first 8 weeks, subjects were titrated to a maximum dose of 40 mg (enalapril) or 80 mg (omapatrilat) as needed, after which subjects who did not achieve the blood pressure goal could have additional antihypertensive agents added through week 24. At 8 weeks, 41% of subjects in the enalapril group and 33% in the omapatrilat group were on the highest recommended doses. Between weeks 8 and 24, 19 to 36% of the enalapril subjects and 13 to 26% of the omapatrilat subjects added antihypertensive therapies. At 8 and 24 weeks, omapatrilat had a significantly greater effect to lower trough blood pressure compared with enalapril, but angioedema, including serious angioedema, was significantly more common in subjects taking omapatrilat.
Grade |
Enalapril N=12557 |
Omapatrilat N=12609 |
Ratio |
Mild |
65 |
161 |
2.5 |
Moderate |
19 |
94 |
4.9 |
Severe |
2 |
17 |
8.5 |
Life-threatening |
0 |
2 |
? |
With these results and the data from the other trials of omapatrilat, the Committee is being asked