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Novartis' Blood-Pressure Drug Tekturna: A Victim of Bad Timing

Adding Novartis' (NVS) blood-pressure medication Tekturna (aliskiren) to standard medical therapy in patients recovering from a heart attack doesn't offer additional benefit and could result in more side effects. Although interviewed specialists suggest it's premature to interpret -- or dismiss -- the drug's effectiveness in preventing end-organ damage, the setback seems likely to hurt strategic efforts to expand Tekturna's franchise beyond hypertension.

Findings from ASPIRE (Aliskiren Study in Post-MI Patients to Reduce Remodeling), one of 14 trials evaluating Tekturna's potential benefit beyond blood pressure reduction, showed that although addition of the drug did help limit changes to the heart's shape and function in patients after heart attack (post-myocardial infarction), the results were not statistically significant.

Tekturna (sold under the brand name Rasilez in Europe), is a first-in-class drug that directly inhibits renin, a rate-limiting enzyme at the top of the renin-angiotensin system (RAS) cascade, one of the key regulators of blood pressure. Approved in 2007, the company is pushing to accelerate and broaden approved indications for Tekturna before the loss of patent protection for its flagship blood pressure treatment Diovan -- where expiration is anticipated in 2011 and 2012 for Europe and the US, respectively.

As the only medicine in the angiotensin receptor blocker (ARB) class approved for treatment in high blood pressure, high-risk heart attack survivors and heart failure, Diovan (valsartan) reached $6 billion in sales last year, compared with $290 million in Tekturna sales for hypertension.

The ASPIRE trial's presenter at the 2010 American College of Cardiology meeting, Scott Solomon of Brigham and Women's Hospital said in written correspondence that the study results were reminiscent of another trial he participated in several years ago, VALIANT, which was designed to compare the additive effect of a second RAS inhibitor, Novartis' ARB Diovan, against standard-of-care, in this case the angiotensin-converting enzyme inhibitor (ACEI) captopril; or the combination of both, when administered to patients at high-risk for -- or already with -- heart failure in the immediate post-MI period. In a cohort of 600 patients, the combination therapy showed no incremental benefit over ACE inhibition or an ARB alone and resulted in increased adverse effects, such as hypotension and hyperkalemia.

Two prior studies with Tekturna (Aliskiren in Left-Ventricular Hypertrophy trial -- ALLAY; Aliskiren Observation of Heart Failure Treatment trial -- ALOFT) did demonstrate positive results in promoting regression of left ventricular mass, a key measure of myocardial end-organ damage.

Heart specialists I spoke with agreed that it would've been a stretch for Tekturna-treated patients to show clinical superiority, as patients in the trial were already receiving the best-of-care, which included treatment with the cholesterol-lowering statins, beta blockers, and ACEI. As explained to me by Alan H. Gradman, a Temple University researcher active in the areas of hypertension and congestive heart failure, the hearts of patients participating in ASPIRE were minimally enlarged -- and much less abnormal -- compared with post-infarct survivors enrolled in landmark trials almost 20 years ago (which confirmed the utility of RAS inhibition (with ACEI) in attenuating ventricular remodeling). Ergo, as there was less potential for the ventricles of the heart to remodel, the ability of any treatment to prevent remodeling was also reduced.

Nonetheless, the collective findings in the post-MI population do not support dual-agent suppression of the RAS at this time, concluded Dr. Solomon.

Ameet Nathwani, Global Head of Novartis' Cardiovascular and Metabolism Development Franchise, confirmed with me that Novartis wouldn't pursue further research in potential outcome benefits afforded by Tektuna therapy in the post-MI setting. With little evidence supporting the clinical superiority of Tekturna over more-established drugs, in my opinion, the company's decision was also influenced by a post-infarct market increasingly crowded with generic entry of current market-leading agents (including Diovan).

The chronic and diverse nature of many cardiovascular diseases offers significant commercial opportunity for Novartis to widen the potential user base for its Tekturna/Rasilez portfolio through expanded labeling. For example, there is a 30 -to- 40 percent re-admission rate among heart failure patients upon returning home from hospitals, said Nathwani.

Unfortunately, Novartis will likely feel the ripple affects of the ASPIRE splash, as supportive data from ongoing trials examining the compensatory benefits of Tekturna in high-risk, hypertensive patients with heart failure or diabetic kidneys is not expected before 2013 -- well after sales for its bestseller Diovan will have evaporated.
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