Boost to shares but not to sales as Vytorin takes middle track

Merck & Co will just have to content itself with waiting and seeing. An interim look at the data from the Improve-It trial of the cholesterol lowerer Vytorin has not supported an early shutdown of the study, so watchers will have to wait until September 2014 to find out whether or not the combination works as well as one of its constituents, Zocor.

The focus now shifts 18 months hence to Improve-It’s final read-out. At that point Vytorin will either squeak to victory over Zocor or narrowly lose to it. In either case sales of the combination are unlikely to change markedly. In fact the main effect of Improve-It may not be on Vytorin but on another class of cholesterol drugs entirely: the much-vaunted PCSK9 inhibitors.

Outcomes

The decision to continue the study is not a disaster for Merck, but it will be a disappointment. Vytorin’s patent expires in 2017 and the New Jersey group will have been hoping for highly positive data and thus an immediate sales boost, perhaps thrusting the drug back into blockbuster territory for another four years (Event – Interim look at Improve-It will indicate Vytorin’s future, February 28, 2013). At least yesterday’s 3% share price rise, adding $4bn to the company’s market cap, will be something of a silver lining.

The implications for PCSK9 inhibitors, which include Regeneron and Sanofi’s REGN727/SAR236553 and Amgen’s AMG 145, are more interesting. These have been shown extremely effective at dropping LDL-C levels, and based on the hypothesis that reducing low-density lipoprotein cholesterol helps prevent strokes, heart attacks and other cardiovascular events, hopes are high.

Hitherto it has been assumed that the PCSK9 drugs could be approved on LDL-C clearance alone, rather than on hard proof that they prevent death and cardiovascular events (AHA – PCSK9 inhibitors continue to impress, November 7, 2012). Failure of Improve-It, which has the cast-iron endpoint of rates of death due to any cardiovascular events, non-fatal coronary events, and non-fatal strokes, means the likelihood of approval on a surrogate endpoint falls.

Analysts at Leerink Swann said that Improve-It would ultimately fail to show Vytorin’s superiority over Zocor, with the absolute LDL difference at the end of treatment likely to be modest, at around 10-12mg/dl, but a trend to benefit would be seen.

They added that the most likely path to approval for PSCK9 inhibitors would involve first getting the nod for a narrow patient population – for instance, patients who do not respond fully to statin therapy – with post-approval outcomes studies being necessary for expansion to a wider population.

But that is by no means definite. If the FDA does demand a pre-approval outcomes trial for the PSCK9 class, their developers face both delay and expense. Improve-It holds the key to more than Merck’s bottom line.

To contact the writer of this story email Elizabeth Cairns in London at elizabethc@epvantage.com or follow @LizEPVantage on Twitter

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