DARAs: an innovative approach to treating disease

The recent approval of Novartis’ Tekturna marked the first new class of antihypertensive drugs to gain the FDA’s blessing in more than 15 years. This development clearly indicates that there continues to be a need for innovative treatments for hypertension despite the broad menu of therapies currently available.

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The recent approval of Novartis' Tekturna marked the first new class of antihypertensive drugs to gain the FDA's blessing in more than 15 years.  This development clearly indicates that there continues to be a need for innovative treatments for hypertension despite the broad menu of therapies currently available.  With this in mind, Pharmacopeia recently advanced into Phase 1 clinical testing a brand new drug class with the potential to treat hypertension.
Known as a Dual-Acting Receptor Antagonist (DARA), this single compound is able to simultaneously block the actions of two different endogenous peptides at their two separate and distinct receptors in the body.  The potential of this new drug class includes the possibility to significantly improve the options available to physicians to treat various cardiovascular diseases, particularly hypertension, compared to compounds presently on the market or in development. 
Hypertension is a well-documented risk factor contributing to the morbidity and mortality of cardiovascular disease.  Presently, an estimated 30 million American adults are diagnosed with hypertension, and there are a wide variety of drug classes approved for treating these patients, including angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, beta-blockers and calcium channel blockers.  While these drugs can be prescribed as monotherapy, many times hypertensive patients are unable to properly control their blood pressure with a single agent.  Consequently, combinations of these drug classes are often required by co-prescription of more than one therapeutic class.  In addition, the need for combination therapy has led drug developers to incorporate more than one active ingredient into a single pill.  Examples of these single pill combination therapies include DIOVAN HCT and LOTREL, both from Novartis, and AstraZeneca's TENORETIC, among others.  With these combination products, patients are able to receive the benefits of multiple drugs without taking multiple pills.   
While mixing two different drugs in one pill has become relatively common, DARA compounds take that concept one step further.  Instead of combining two different active compounds in one pill, DARA compounds are single molecules that possess the activities of two proven therapeutic classes.  Researchers believe that such compounds may ultimately provide patients with efficacy, safety and convenience benefits as compared to currently available hypertension treatments. 
Pharmacopeia's efforts in this area have focused on a DARA compound that works by selectively blocking the activities of angiotensin II (AII) and endothelin 1 (ET1), at their respective receptors.  AII and ET1 are two of the most potent vasoactive peptides known and are believed to play a role in controlling both vascular tone and the pathological tissue remodeling associated with a variety of diseases including diabetic nephropathy and heart failure.  Currently, angiotensin receptor blockers (ARBs), which inhibit the activity of AII, are widely used as a treatment for hypertension, heart failure and diabetic nephropathy.  At the same time, there is a growing body of data of that demonstrates the potential therapeutic benefits of ET receptor antagonists (ERAs) in blocking ET1 activity. It is also known that AII and ET1 work together in blood pressure control and pathological tissue remodeling.  For example, ARBs not only block the action of AII at its receptor, but also limit the production of ET1. Similarly, ERAs block ET1 activity and inhibit the production of AII. Consequently, simultaneously blocking AII and ET1 activities may offer better efficacy than blocking either substance alone.
In rodent models of human hypertension, the combination of an ARB and an ERA results in more than an additive effect.  Furthermore, in multiple animal models of heart failure, the combination of an ARB and an ERA results in improvements in both function and tissue remodeling - parameters not seen with either agent alone.  A DARA compound that is able to simultaneously inhibit both AII and ET1 activity may possess significant potential in treating hypertension.
Such a DARA compound may be especially valuable for patients whose blood pressure resists control even when multiple antihypertensive drug classes are employed.  Alarmingly, an estimated 10 million American adults are not achieving their desired blood pressure despite receiving three or more drug classes.  For these patients, effective blood pressure control represents a significant unmet medical need.  Based on the therapeutic benefits anticipated from DARA compounds, as well as results from extensive preclinical research conducted to date, it is believed that this class of drugs may be able to offer these patients the opportunity for better control of their high blood pressure.
One of the more serious complications of persistent high blood pressure, particularly for those also suffering from diabetes, is chronic kidney disease (CKD).  Currently it is estimated that more than 20 million Americans suffer from CKD.  If not controlled, chronic kidney diseases such as diabetic nephropathy lead to dialysis, and ultimately the need for a kidney transplant.  Presently, ARBs are the standard of care for patients with diabetic nephropathy.  However, results from Phase 2 clinical trials conducted by Speedel suggest that co-administration of an ERA and an ARB leads to additional benefits over either alone for diabetic nephropathy patients.  Since patients with diabetic nephropathy frequently have concomitant high blood pressure, DARA compounds may be particularly well-suited to treat this patient population.
Hypertension and diabetic nephropathy are just two examples of disease areas in which the DARA concept may lead to improved therapies for patients.  Any disease with multiple underlying causes or contributors may potentially be a candidate for treatment with appropriate DARA compounds. 
Dr. Leslie J. Browne is President and CEO of Pharmacopeia

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