CHICAGO — Two trends are emerging in the development of investigational antihypertensive drugs.
Look for more fixed-dose combinations and agents with beneficial effects beyond blood pressure lowering alone, said Dr. George Bakris, director of the hypertensive diseases unit and professor of medicine at the University of Chicago.
“There's going to be a lot more in the armamentarium of combination therapy,” he said at a meeting sponsored by the International Society on Hypertension in Blacks. “Approximately 76% of all the 75 million hypertensives require two or more antihypertensive agents, and people are sick of taking pills.”
Takeda Pharmaceuticals recently launched a phase III trial of its investigational compound TAK-491, an angiotensin receptor blocker (ARB), combined with the diuretic chlorthalidone in patients with moderate to severe hypertension. Takeda expects TAK-491 to show stronger antihypertensive action and to have a profile in improving insulin resistance and decreasing proteinuria that is superior to existing ARBs. The company also expects that it will succeed its current mainstay product candesartan, also an ARB.
“It's not your mother's ARB,” Dr. Bakris said. “It could be the ARB tailored for the metabolic syndrome.”
Boehringer Ingelheim recently announced effective 24-hour blood pressure control with its investigational combination of the ARB telmisartan and the calcium channel blocker amlodipine in hypertensive patients at risk of cardiovascular events and those not controlled with amlodipine alone.
In April 2009, the Food and Drug Administration approved Exforge HCT, the only antihypertensive agent to include three medications—amlodipine, valsartan, and hydrochlorothiazide—in a single pill.
Neutral Endopeptidase Inhibitors
Neutral endopeptidase (NEP) inhibitors also are being given a second look, this time in combination with ARBs. NEP is the major enzymatic pathway of degradation of natriuretic peptides, which are thought to have such beneficial effects in hypertension as vasodilation, natriuresis, and inhibition of the sympathetic nervous system.
The investigational drug omapatrilat (Vanlev), which combined inhibition of both ACE and NEP, appeared to be a powerhouse, beating such leading agents as losartan and amlodipine. But its new drug application was withdrawn for a second time in 2002 because of reports of life-threatening angioedema.
“Theoretically, the synergy from an ARB/NEP combination should be similar. And because of lesser bradykinin effects, the risk is lower for angioedema, as ARBs have about a 10% incidence of angioedema, compared with ACE inhibitors,” Dr. Bakris explained in an interview. “The role of NEP is unclear since no one knows the mechanism of angioedema, but it is very rare in Caucasians and has an incidence of less than 0.01% in African Americans.”
Several ARB/NEP inhibitors, including MDL 100240 and MDL 100173, are in development, with these combinations expected probably in late 2010-2011, he said.
Endothelin Inhibitors
Finally, researchers are investigating combined ARB and endothelin inhibition. Endothelin (ET-1) is an amino acid peptide produced by the vascular endothelium and increases angiotensin II, aldosterone, antidiuretic hormone, thrombin, and reactive oxygen species. Studies have shown ET-1 is a powerful vasoconstrictor (Radiology 2001;219:419-26) and plays a role in salt retention (Circulation 2001;103:263-8).
Dr. Bakris noted that Gilead Sciences made a splash earlier this year when it released interim results showing dramatic additional blood pressure reductions with its selective endothelin A receptor antagonist darusentan in patients who had resistant hypertension despite maximal doses of a three-drug regimen that included a diuretic.
The phase III DAR-311 trial, also known as DORADO, met its coprimary efficacy end points, reporting that 14 weeks of once-daily oral darusentan 50 mg, 100 mg, and 300 mg significantly reduced mean trough sitting systolic BP by 18 mm Hg at the two higher doses and mean trough sitting diastolic BP by 10 mm Hg at all three doses.
“I helped design this study and none of us thought we would get this kind of effect,” he said. “This is definitely something that will be in the armamentarium for resistant hypertension,” Dr. Bakris said.
He suggested darusentan could be available in 6-9 months, but cautioned that it should not be considered for first-line treatment.
“In case you think this is such a gorilla you should start with it, that is not how these studies were designed and you should not extrapolate to that,” he said. “It would be wrong.”
He noted that treatment-related peripheral edema/fluid retention of about 1 L was an issue in about one-third of patients at each dose.
Dr. Bakris disclosed receiving research support from the Juvenile Diabetes Research Foundation, GlaxoSmithKline, Forest Labs, and CVRx, and serving as a consultant or speaker for GSK, Merck, Novartis, Boehringer Ingelheim, Takeda, Abbott, Walgreens, BMS/Sanofi, Gilead, and Forest.