Novartis Looks at Combination Pills to Fix Hypertension Franchise

Novartis could find its leadership position in blood pressure therapies challenged in the next two years, owing to generic intrusion on its flagship anti-hypertensive drug Diovan. Near-term, with no novel agents emerging from its  research pipeline, the drugmaker is reaching into its life-cycle playbook and introducing a number of new fixed-dose combinations to stem expected market share loss.

Seven medicines within its BP franchise, including Diovan, are available in most markets worldwide, with the three biggest markets accounting for 81 percent of total pharmaceutical sales:  the United States (33 percent), Europe (38 percent), and Japan (10 percent).

Diovan (valsartan) works primarily by blocking a protein called angiotensin (AT) II, which causes blood vessels to constrict, driving BP up. The drug’s blockade of AT receptors (subtype 1) results in the relaxation and dilation of blood vessels. As blood flows more easily the BP is reduced (as well as stress on the heart). The patent on Diovan expires in the major countries of the European Union in 2011, in the U.S. in September 2012, and Japan in 2013. However, sales could erode much sooner, as the patent on the first drug in this class, Cozaar (losartan) made by Merck, expires in certain EU countries this year and in the U.S. in April 2010. Latest nine-month sales for Diovan were $4.4 billion, almost 21 percent of total global pharmaceutical sales, according to the third-quarter regulatory filing with the SEC.

Motivated by cost-saving benefits, the threat of generic substitution by healthcare organizations is real. To wit:

• Diovan’s BP medicine called Lotrel, a single-pill combination of the angiotensin-converting enzyme (ACE) inhibitor benazepril, used in Lotensin (U.S.) / Cibacen (outside the U.S) and the generic calcium channel blocker (CCB) amlodipine, has a valid U.S. patent until 2017. Undaunted, Teva Pharmaceuticals challenged the formulation with a “launch at risk” strategy (flooding the market with cheap imitations before a trial date has been set, hoping to wind down the clock and avoid potentially huge monetary damages if Novartis were to prevail in court). Sales of Lotrel plummeted from $1.35 billion in 2006 to $385 million in 2008.

Novartis’ second-in-command BP medicine is Exforge, a single-pill combination of its AT-II receptor antagonist Diovan and the CCB amlodipine. Available in both the U.S. and EU since 2007, the drug posted nine-month sales of $475 million. The company received approval for a brand extension in the EU for Exforge HCT, a new 3-in-1 treatment for high blood pressure last month. Exforge HCT, which is Exforge plus plus the common diuretic hydrochlorothiazide (HCT) became available in the U.S. in April 2009. While these agents will offer considerable improvements in convenience over currently available fixed-dose combinations, interviewed experts express differing views on their likely uptake.

In Hypertension - August 2009, co-author Caroline Gates, an analysts at pharma think tank Decision Resources, reported that some surveyed experts welcomed the greater convenience offered with a reduced pill burden; on the flipside, others nodded their preference for single agents — in order to titrate individual doses on a patient-by-patient basis, especially in cases of advanced hypertension where at least three drugs are typically required to control blood pressure.

Unfortunately, leveraging brand name through the appeal that additional Exforge fixed-dose combinations offer (improved compliance and greater convenience) won’t even amount to a stop-gap fix for Novartis. Although the drug’s patent on its fixed-dose formulation does not expire in the U.S. until September 2012, at least one company (unidentified) filed an abbreviated new drug application (ANDA) with the FDA back in October 2007 — signaling intent to market a generic version of Exforge. If it is Teva (as I suspect), given their successful “at risk” launch of Lotrel, they will likely challenge the patent and launch prior to 2012.

Tekturna/Rasilez (aliskiren), the first new type of high blood pressure medicine in more than a decade, is the company’s best near-term hope in sustaining its hypertensive franchise. Tekturna blocks the enzyme renin, the first chemical in the cascade of hemodynamic events that cause the narrowing of blood vessels. Its patent runs to 2018 in the U.S. and between 2015 and 2020 in other markets.

In addition to Tekturna, management is counting on four more single-pill combination therapies (that include aliskiren) to supplant sales lost to generics, including the recently FDA-approved Tekturna and Diovan combination pill called Valturna.

Management anticipates all of these therapies should be approved before the loss of market exclusivity for Diovan in the U.S. come 2012.

Novartis is looking to widen the potential user base for its Tekturna/Rasilez portfolio through expanded labeling, too. The heart and kidney protection potential of Tekturna/Rasilez, in addition to its blood pressure lowering ability, is currently being investigated in the ASPIRE HIGHER program, the largest ongoing cardio-renal outcomes program worldwide, involving more than 35,000 patients in 14 trials.

The nonsensical Baseball Hall-of-Famer Yogi Berra said it best: “You’ve got to be very careful if you don’t know where you’re going, because you might not get there.” Sales for the Tekturna/Rasilez franchise totaled $202 million for the nine-months ended September — a long way from $4.4 billion.