Medical researchers often find tantalizing hints about the causes of disease when they spot biomolecules that seem to be closely associated with the onset of an illness—like the amyloid plaques seen in the brains of people with Alzheimer’s disease. Pharmaceutical companies often run with those hints, creating experimental drugs targeted at those suspect biomolecules.
But are the suspect disease markers actually causing the illness, or are they just incidental symptoms or byproducts of it? Will a drug targeting a disease marker do anything to combat the disease?
For a biomarker called Lp-PLA2 that’s long been associated with heart attack risk, answers to that question will start coming by the end of this year, when UK-based GlaxoSmithKline releases initial results from the first of two huge late-stage clinical trials of its experimental drug darapladib. Darapladib inhibits the action of the Lp-PLA2 enzyme, whose full name is lipoprotein-associated phospholipase A2.
It’s not clear yet whether high Lp-PLA2 levels in the bloodstream cause heart attacks and strokes, or are merely a warning sign that one might be impending. But if darapladib staves off these events in people with hardening of the arteries, Glaxo could have an international blockbuster drug on its hands. And a success for Glaxo could also be a bonanza for the small South San Francisco company diaDexus. Nearly all of diaDexus’s revenues come from the sale of a single product: a diagnostic test for heightened levels of Lp-PLA2.
At low levels, the enzyme has a normal, beneficial function in healthy people—it scavenges cholesterol from the walls of arteries and helps clear it out, says diaDexus CEO Brian Ward.
“You need a little bit of it,” Ward says. But a build-up of Lp-PLA2 is a danger sign that hardened deposits of plaque in the arteries are more likely to break apart, sending clots into the vessels that could cut off the blood supply to parts of the heart or brain.
Physicians use the diaDexus test, called PLAC, to find out how likely it is that their patients who have a few risk factors for cardiovascular disease, such as age or high blood pressure, will actually suffer a heart attack or stroke. This can happen even in patients with low cholesterol, Ward says.
“We save lives because we uncover the hidden risk,” Ward says. Medicare, and about 50 percent of private insurers, reimburse for the diaDexus test in its role as a mere signal of developing danger that may stem from causes other than the Lp-PLA2 marker itself.
But if Glaxo’s trials show that blocking the activity of Lp-PLA2 fends off a cardiovascular crisis, Ward says, the enzyme could be redefined as a risk factor in itself. This could help diaDexus overcome remaining reimbursement barriers for the PLAC test, and spur physicians to order it, he says. The test could also become the companion diagnostic to identify patients who might benefit from Glaxo’s darapladib.
Since its founding in 1999, the fortunes of diaDexus have been intertwined with the big pharmaceutical company’s. DiaDexus was formed as a joint project of Incyte Pharmaceuticals and SmithKline Beecham, which merged with GlaxoWellcome to form GlaxoSmithKline in 2001. From SmithKline Beecham, diaDexus received exclusive rights to develop a diagnostic test for Lp-PLA2. DiaDexus earned FDA clearance to market its test in 2003 for heart disease risk and in 2005 for the risk of stroke.
The test was designed to alert doctors when an unseen process was beginning to raise the cardiovascular risk of patients who have never suffered heart disease or stroke. When people develop plaque deposits in their arteries, these buildups can remain stable for a time under a hardened “cap.” But the deposits can later become inflamed, unstable, and prone to rupture. An increase in Lp-PLA2 levels is associated with that inflammatory process, Ward says.
Doctors can now order the test as part of an advanced lipid profile for patients who already have two or more risk factors, including family history, excess weight, diabetes, age over 50, high cholesterol, and smoking. DiaDexus estimates that about 85 million adults in the United States have two or more of these risk factors. If Lp-PLA2 levels are high, physicians may decide to start treatment with statin drugs or other treatments, Ward says. Heart attack and stroke are among the top causes of death in the United States.
However, the financial road has been rocky for diaDexus, which was delisted from the NASDAQ exchange in 2004. In 2010, the company gained an influx of cash through a reverse merger with the foundering vaccine developer VaxGen. Shares in the merged entity now trade in over the counter markets under the ticker DDXS. The share price dropped below 30 cents in October of 2012, but has climbed to about $2 a share since then.
Ward, a former board member who became CEO in 2011, says a new executive team and selling strategy have revived the company over the past two years. Revenues rose from $16.3 million in 2011 to $20.7 million in 2012, when the company’s loss was $2.7 million. In diaDexus’ second quarter of 2013, total revenues rose 22 percent compared to the same period last year, the company reported.
DiaDexus is seeking FDA approval for a newer version of the PLAC test that could be used by a greater number of labs in hospitals and clinics. Specialty labs are now diaDexus’ largest customers. Plans are also in the works to develop new types of cardiovascular diagnostics. But the Glaxo trials may also hold out the potential for greater growth.
While diaDexus was striving to expand its Lp-PLA2 testing business, Glaxo was collaborating on the development of darapladib with Human Genome Sciences, which Glaxo acquired in 2011 for $3 billion. The collaboration has already produced belimumab (Benlysta) a new drug for the treatment of lupus erythematosus approved by the FDA in 2011.
Mid-stage trials for darapladib didn’t meet the primary goals set by Glaxo, but the company saw enough promise to launch two Phase III trials with a total of more than 28,000 participants. In those trials, the newer version of diaDexus’s Lp-PLA2 test is being used to find patients with elevated levels of the enzyme.
Summary results of the first trial, called Stability, are expected by the end of the year, Ward says. In that trial, participants with cardiovascular disease are given darapladib or a placebo, along with standard treatments such as statins. Results from the second trial, in participants who have recently been hospitalized, are expected in March.
But more detailed data will be released later, and it may indicate which subgroups respond most to Glaxo’s drug, if any. With the PLAC test, Glaxo will be able to see which participants started with very high levels of Lp-PLA2, and which had more moderately elevated levels.
If the trial participants who received darapladib have fewer heart attacks or strokes than the control group, it could mean that Lp-PLA2 somehow causes stable plaques in the arteries to rupture. But exactly how that happens still remains to be explored, Ward says.
“That’s a difficult question to answer,” Ward says. “And if it’s a risk factor, what causes it to click on?”
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