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UPDATED: GlaxoSmithKline loses its first big PhIII bet on heart drug darapladib

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GlaxoSmithKline's blockbuster heart drug hopeful darapladib failed to hit the primary endpoint in its first huge Phase III study, dealing a severe setback for another one of its top late-stage prospects. The pharma giant ($GSK) reported that the drug did not produce a statistically significant improvement in the risk of heart attack, stroke or death, though it added that "greater reductions" for some of the secondary endpoints warranted careful follow-up review as investigators considered its potential.

Only yesterday, Reuters noted that analysts had set the value of this high-risk program at a megablockbuster $10 billion per year. Now, GSK may be considering how much it will have to write off the books.

GlaxoSmithKline invested heavily to recruit 16,000 patients with acute coronary syndrome for the study. By inhibiting the enzyme Lp-PLA2, investigators had hoped that it could reduce the arterial plaque in patients, potentially offering a big improvement for their health. GSK had wrapped up all rights to the drug with its acquisition of Human Genome Sciences and R&D chief Moncef Slaoui had touted darapladib as one of the company's most innovative therapies, alongside the cancer vaccine MAGE-A3. Now both therapies have flunked their first late-stage test--though both are still in the clinic and are still considered top prospects at the company.

As in most such cases, GlaxoSmithKline will wait for an upcoming scientific conference to lay out the details of the failure and where it may see potential for niche uses. The company has another 13,000-patient study, SOLID-TIMI 52, underway, which will see if the drug can prevent a second heart attack, though expectations are likely to be very low now that the first study failed.

Panmure Gordon's Savvas Neophytou, who downgraded GSK's stock today as it slipped 1.6% on the news, said that he was expecting a writedown at GSK, adding that any approval based on the second trial alone would be hard to come by now that the first big study has ended in failure.

"We make some adjustments to forecasts, mainly assuming a £150m ($238 million) write-down in the fourth quarter even though a second Phase III trial is still ongoing with results expected in the first half of 2014," noted Neophytou, according to The Guardian. "Even if that trial was successful, we believe it will be difficult to gain market registration on one trial alone."

Bernstein's Tim Anderson wasn't looking for success with darapladib, so he counts himself as unsurprised by today's announcement. But he added in his note that the failure raises a serious question for Glaxo about its decision-making abilities regarding the late-stage pipeline. "It might be argued that this was the 'old' GSK and not the 'new' GSK, and that if the clock could somehow be rolled back its R&D decision makers would not advance products like these into late-stage development. It has been a red flag that with both candidates, no other pharmaceutical companies were chasing the same dream."

A serious problem for GSK is a major setback for South San Francisco-based diaDexus, which provided the diagnostic used in the study. Its shares ($DDXS) plunged 53% this morning, dropping to 79 cents a share. 

Don't look for GSK to throw in the towel--yet.

Patrick Vallance, head of GSK's pharma R&D

"Given the level of patient need in this area, we continue to investigate the role of Lp-PLA2 inhibition in coronary heart disease and other diseases," said Patrick Vallance, the head of GSK's pharma R&D, in a statement. "We will now work to better understand the data, including evaluation of the patient sub-groups, and await the outcome of a second Phase III study of darapladib in acute coronary syndrome, called SOLID-TIMI 52, to determine our next steps."

GlaxoSmithKline may have some notable trial setbacks for the year, but it also has scored a slate of regulatory approvals that is ushering in some badly needed new products. None of those new drugs, though, have the kind of megablockbuster prospects that can sustain a big company for years. 

- here's the release
- read the report from The Guardian

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