Novartis' Tekturna looks troubled

News that Tekturna will no longer be sold in combination with commonly used hypertension medicines is an ominous sign for the beleaguered Novartis drug.

For a long time a product of questionable potential, the pharma giant has struggled to drive demand and the huge clinical programme conducted to try and carve out a niche in the increasingly generic high blood pressure market means Tekturna has yet to make a profit, according to the company (Quality of new products remains low, March 6, 2009). As Novartis’ tenth most valuable product its potential loss will be manageable but, as $6bn Diovan enters its final few months of patent protection, the company’s huge hypertension franchise faces a painful 2012.

Detrimental impact

An independent data monitoring committee this week stopped the Altitude trial of Tekturna in diabetics with reduced kidney function after finding increased incidence of non-fatal stroke, renal complications, hyperkalemia and low-blood pressure in patients taking the renin inhibitor. The committee identified no clinical benefit to patients.

Given that in the trial Tekturna was taken in addition to angiotensin converting enzyme inhibitors (ACEs) or angiotensin receptor blockers (ARBs), Novartis will stop promoting it in combination with drugs in those two classes, as is allowed on the label.

Novartis was clearly setting a challenge for itself. The population in the trial was a sick one – patients had diabetes plus diabetic nephropathy, or reduced kidney function plus previous heart attack or stroke, heart failure or coronary artery disease. The study overall measured if patients taking Tekturna were less prone to cardiovascular events or end-stage renal disease than those taking placebo. Unfortunately for Novartis, the trial showed just the opposite.

Aside from raising serious question marks over the future of the product, the setback disrupts Tekturna’s immediate label expansion plans. With its third quarter 2011 results, Novartis listed an anticipated filing in diabetic nephropathy in 2012. It had anticipated an additional filing in 2013 to add prevention of cardiovascular events in heart failure patients to the label, but clearly those plans have been scuttled by the Altitude findings.

Fallout for Novartis

Tim Race, a healthcare analyst at Deutsche Bank, believes the fallout from the Altitude study for Novartis will come in the shape of a big downsizing of the company’s US sales force next year. With 1500-2000 primary care sales reps in the US, he expects half of these to be removed as a direct result of Tekturna failure, and the loss of Diovan in September.

Despite its imminent demise, Diovan remains Novartis’ third most valuable product, with an NPV of $9.34bn, according to EvaluatePharma. Tekturna is worth $3.58bn, with forecast sales of $1.37bn by 2016, a figure that looks set to at decline substantially.

Diovan’s days have long been numbered and hopes for Tekturna were low; Novartis can weather this storm. All eyes are on the company's growth stories for now, in particular Gilenya – recent news of the sudden death of a patient taking the MS drug is a worry and how this story develops, with the FDA announcing yesterday a review of this event, will be watched with interest next year.

Add on to what?

Had the Altitude study been positive Tekturna, as one of the few branded hypertension drugs being supported by an active marketing force, would have received a real boost.

“A positive outcome study could have made it a Diovan sized product,” Mr Race said. The product's future is now a lot less certain, he believed.

“It has no real place in the market on its own, just as an add on – to what is the question.”

Novartis has several Tekturna combinations on the market. Valturna, which combines Tekturna with the ARB Diovan, is an obvious casualty of the Altitude study – around half of Tekturna sales are thought to come from combining the drug with an ARB or ACE inhibitor. Other combination products include pills combining Tekturna with amlodipine, a widely-used calcium-channel blocker, and with the diuretic hydrochlorothiazide.

Off target

Tekturna works by directly targeting a blood enzyme called renin, a component of the renin-angiotensin system, essentially a cascade of enzymes and hormones that lead to increased blood pressure. The ARBs and ACE inhibitors also target renin, albeit indirectly, and work through the same system.

Although using two drugs with different mechanisms might logically seem to offer a more potent way of lowering blood pressure, dual inhibition of the renin-angiotensin system with an ARB and an ACE inhibitor had already been essentially ruled out by the Ontarget trial. Published in 2008, the study found that a combination of the ACE, ramipril, and the ARB, Micardis, increased the risk of renal dysfunction when compared to ramipril alone.

Previous trials had made the case for the dual combination therapy based on the surrogate endpoints of reduced protein in the urine – also a finding of the Avoid study that combined Tekturna with the ACE, Cozaar.

As such, combining two agents that target renin was already known to be ineffectual, if not detrimental. Treatment guidelines in countries like Canada already explicitly guide against combining these agents.

Hence low hopes for the Altitude study, which really confirms what those in the medical community were already suspecting. 

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