Crunch time for GlaxoSmithKline's big heart drug bet

Reuters

* 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 inGlaxoSmithKline are about to learn if a big gamble on anew kind of heart medicine has paid off, with modestexpectations creating a potentially big share price boost if thenews is good.

Britain's biggest drugmaker hopes its once-daily pilldarapladib can prevent heart attacks and strokes by fightingclogged arteries in a completely different way fromcholesterol-lowering drugs.

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

In theory, darapladib could become a $10 billion-a-yearseller, industry analysts believe, making it GSK'sbiggest-ticket pipeline bet.

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

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

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

Certainly, Bert Hofman, a professor of epidemiology atErasmus Medical Center in Rotterdam, thinks GSK is on tosomething with darapladib.

Hofman was an early pioneer in researching the connectionbetween an enzyme called Lp-PLA2, which darapladib is the firstdrug to inhibit, and arterial plaques. He is not involved in thelate-stage trials.

"The evidence that Lp-PLA2 is causally related to coronaryheart disease and stroke is really quite strong," he toldReuters. "So, in principle, this is an important and promisingapproach."

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

The first trial, known as STABILITY, has enrolled nearly16,000 patients with coronary heart disease and is measuringwhether darapladib can safely reduce the chance of them having aheart attack or stroke.

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

Hofman said GSK, which has said there should be some PhaseIII data this year with more to come next year, probably had abetter chance of success in the second study, given the drug'santi-inflammatory mechanism of action.

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

POTENTIAL GAME CHANGER

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

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

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

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

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

GSK has had some notable successes with its new drugs thisyear, including approvals of new medicines for cancer, lungdisease and HIV. But it also had disappointing clinical resultswith another high-risk product in September, its MAGE-A3 cancervaccine for melanoma.

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