Silent, yet deadly

Hypertension, characterised by a consistently elevated blood pressure, affects approximately one in four adults in the US and UK, and around one billion people worldwide.

This silent killer, as it is known, is generally asymptomatic and can have serious consequences if left untreated, leading to stroke, heart attack, ischaemic heart disease, heart failure, renal dysfunction and loss of vision.

Yet, even among treated patients, adequate blood pressure control is achieved in less than a third of cases. According to the findings of the Third National Health and Nutrition Examination Survey (NHANES III, phase II), of an estimated 53 per cent of US patients being treated for hypertension with prescription drugs, only 27 per cent had the condition under control.

In fact, non-optimal blood pressure control is responsible worldwide for 7.1 million deaths annually and the loss of 64.3 million disability-adjusted life years.

One of the main reasons for inadequate disease control is lack of compliance with therapeutic regimens. Achieving target blood pressure generally requires using more than one antihypertensive. Patients are usually prescribed a combination of antihypertensive medications from the following classes: diuretics (loop diuretics, thiazides, thiazide-like diuretics and potassium-sparing diuretics), adrenergic receptor antagonists (a- and B-blockers), vasodilators, calcium channel blockers (dihydropyridines and non-dihydropyridines) and angiotensin-converting enzyme (ACE) inhibitors.

Unfortunately, patient compliance with complex regmens can be poor. Some of the more promising developments in the pipeline offer potential solutions to the problem of compliance. These include the first renin inhibitor, aliskiren, an angiotensin therapeutic vaccine, controlled-release carvedilol and fixed combination amlodipine/valsartan. Other drugs of note include darusentan and clevidipine for the treatment of resistant and severe hypertension, respectively.

Novel therapies
Renin inhibitors, the first novel antihypertensive class to be developed in over a decade, suppress the renin angiotensin system at its point of activation. Inhibition of plasma renin activity is believed to be crucial in end-organ protection, and serves as a surrogate marker for several cardiac and renal diseases.

Novartis' aliskiren (Rasilez) not only addresses the problem of compliance, but promises additional benefits in terms of sustained disease control, end-organ protection and prevention of 'rebound` hypertension.

Research has shown that oral aliskiren, administered once daily, is well tolerated and provides a sustained 24-hour reduction in blood pressure. Further, a pooled analysis of data from phase II/III trials in 7,060 patients with mild-to-moderate hypertension confirmed the safety and efficacy of aliskiren over a period of six to 52 weeks. Reductions in blood pressure were independent of age, gender or race.

Additional phase III data, (presented at the World Congress of Cardiology) illustrated the benefits of aliskiren alone or combined with the diuretic, hydrochlorothiazide, the calcium channel blocker, amlodipine, or the ACE inhibitor, ramipril.

New drug applications for aliskiren have been accepted in the US and Europe; aliskiren is currently in phase III testing in Japan.

The angiotensin inhibitor vaccine from Protherics is a promising new strategy in the treatment of hypertension. The vaccine's key component, angiotensin, is delivered with CoVaccine's adjuvant comprising sucrose fatty acid sulphate ester, which appears to increase both humoral and cell mediated immune responses following intramuscular administration.

This vaccine, designed to elicit the production of antibodies to angiotensin I, should improve patient compliance. With its envisaged slow onset and sustained effect, it has the potential to be used alone, or in combination with other medications. Phase I trials are underway in the UK, with a phase II proof-of-concept study scheduled to commence in 2007.

CYT 006 AngQb, from Cytos Biotechnology, is another new therapeutic vaccine in development. The product, designed to generate an anti-angiotensin II antibody response, elicited a strong but transient immunological response in 16 normotensives. Based on these results, Cytogen is continuing with this phase I/II trial in 72 hypertensives.

New for old
Among the new approaches being investigated for existing drugs is a combination of two of the most commonly prescribed antihypertensives, amlodipine and valsartan (Exforge), by Novartis.

The drug, which combines two complimentary mechanisms of action, via use of the calcium channel inhibitor, amlodipine, and the angiotensin II antagonist, valsartan, into a single orally administered fixed combination, has been effective and well tolerated to date. A phase III trial of amlodipine/valsartan (administered once daily) versus lisinopril/hydrochlorothiazide in 130 patients with uncomplicated hypertension, demonstrated the efficacy of amlodipine/valsartan in terms of mean sitting blood pressure. New drug applications have been accepted in the US and EU.

GlaxoSmithKline is developing a once-daily controlled-release formulation of carvedilol phosphate capsules to improve patient compliance and enhance dosing-flexibility. This new formulation of carvedilol, a non-selective B- and a-1-blocker with peripheral vasodilating activity, uses Flamel Technologies` Micropump (a microdevice for oral delivery of small molecules which permits extended release). It has been associated with clinically meaningful blood pressure reductions in a dose-dependent manner over 24 hours and is preregistered in the US.

Oral darusentan is being developed by Myogen as a potential 'add-on' treatment for resistant hypertension. In a phase II trial, this selective endothelin receptor antagonist effectively reduced systolic blood pressure in 115 patients with refractory disease (who were receiving treatment with three other anti-hypertensives). Darusentan is being tested in phase III trials (DORADO: DAR-311, DAR-312) in the US and Europe; DAR-311 has been initiated.

Biomarin Pharmceutical has also initiated a phase II trial of sapropterin in 116 patients with poorly controlled hypertension.

The Medicines Company is currently developing clevidipine, a short-acting calcium channel antagonist, for the treatment of perioperative hypertension in the US. Following the completion of two phase III trials, ESCAPE and ECLIPSE, in patients undergoing cardiac surgery, the Medicines Company initiated VELOCITY (a phase III trial in patients with severely elevated blood pressure).

The gold standard
Renin inhibitors could be the new gold standard. However, the selection of antihypertensive medications will need to be tailored to individual patient needs. Each of these new drugs could potentially have a place in the treatment of hypertension.

The author of Pharmaceutical Marketing`s December Pipeline contribution is Liana Siqueira of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight.