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Crunch time for GlaxoSmithKline's big heart drug bet

* First Phase III trial data on darapladib due shortly

* GSK sees once-daily pill as new way to fight heart disease

* Analysts wary after lack of evidence in Phase II

* Consensus forecasts point to $605 mln sales in 2018

* Billions of dollars upside if clinical trials succeed

By Ben Hirschler

LONDON, Nov 11 (Reuters) - Cardiologists and shareholders in GlaxoSmithKline are about to learn if a big gamble on a new kind of heart medicine has paid off, with modest expectations creating a potentially big share price boost if the news is good.

Britain's biggest drugmaker hopes its once-daily pill darapladib can prevent heart attacks and strokes by fighting clogged arteries in a completely different way from cholesterol-lowering drugs.

The first of two large late-stage studies into the product, which targets an enzyme linked to artery-clogging plaques, was due to wrap up last month, according to the U.S. National Institutes of Health's clinicaltrials.gov website. That suggests news is imminent.

In theory, darapladib could become a $10 billion-a-year seller, industry analysts believe, making it GSK's biggest-ticket pipeline bet.

In practice, there are major doubts about its prospects, after mixed evidence to date, and current consensus forecasts point to annual sales of only $605 million in 2018, according to Thomson Reuters Pharma.

Barclays analysts see just a 10 percent probability of the drug succeeding, which they say points to a potential 12 percent boost to GSK's valuation if Phase III trial results are positive, with a modest 2 percent downside if it fails.

Morningstar gives slightly better odds of 30 percent, noting that although an earlier Phase II study in 2008 failed to meet its primary endpoints it did show a positive trend.

Certainly, Bert Hofman, a professor of epidemiology at Erasmus Medical Center in Rotterdam, thinks GSK is on to something with darapladib.

Hofman was an early pioneer in researching the connection between an enzyme called Lp-PLA2, which darapladib is the first drug to inhibit, and arterial plaques. He is not involved in the late-stage trials.

"The evidence that Lp-PLA2 is causally related to coronary heart disease and stroke is really quite strong," he told Reuters. "So, in principle, this is an important and promising approach."

However, even if darapladib does have a beneficial effect, it is quite possible that this will not be seen consistently in both of the two big Phase III studies set to report data.

The first trial, known as STABILITY, has enrolled nearly 16,000 patients with coronary heart disease and is measuring whether darapladib can safely reduce the chance of them having a heart attack or stroke.

The second 13,000-patient study, called SOLID-TIMI 52, is due to complete in March 2014 and is looking at patients who have already suffered an acute coronary event. It will assess if darapladib can prevent a secondary attack.

Hofman said GSK, which has said there should be some Phase III data this year with more to come next year, probably had a better chance of success in the second study, given the drug's anti-inflammatory mechanism of action.

It is designed to prevent the expansion of the so-called necrotic core of arterial plaques, which can lead to a rupture and blockage of blood vessels, triggering a heart attack.


With nearly 29,000 patients, the combined Phase III programme is one of the largest ever conducted for a heart drug and it has cost GSK hundreds of millions of dollars to run.

GSK also ramped up its exposure to darapladib last year when it gained full control of the product, along with lupus drug Benlysta, by buying U.S.-based Human Genome Sciences.

The new drug should offer something above and beyond the hugely successful cholesterol-lowering statin class of drugs, making it a potential "game changer" in the management of heart disease, according to Deutsche Bank.

Doctors believe it could be used alongside statins, such as Pfizer's Lipitor, which is now generically available, and AstraZeneca's Crestor, as well as complementing a new class of cholesterol medicine known as PCSK9s.

Injectable PCSK9 drugs, which have cut levels of "bad" LDL cholesterol dramatically in tests, are being developed by Sanofi , Amgen and other firms.

GSK has had some notable successes with its new drugs this year, including approvals of new medicines for cancer, lung disease and HIV. But it also had disappointing clinical results with another high-risk product in September, its MAGE-A3 cancer vaccine for melanoma.