Darapladib failure is a disappointment for a field struggling for direction
Phase III success was not expected for GlaxoSmithKline’s darapladib, but today’s drop in the company’s share price all the same reveals the potential it held. Heart disease remains the biggest killer in the western world and represents a huge cost to healthcare systems, but researchers are struggling to find drugs that have an impact.
Darapladib, an Lp-PLA2 inhibitor, looks likely to join the list of failed cardiovascular projects. Epidemiology data point to a strong link between Lp-PLA2 levels and cardiovascular risk, but the darapladib results suggest that this link is not so straightforward. As trial after trial fails to prove the benefit of other assumedly beneficial heart drugs like HDL boosters or triglyceride-lowering therapies, it is clear that the cardiovascular field has a long way to go before it figures out which markers matter.
Glaxo said today that the Stability trial had failed to hit its primary endpoint, time to first occurrence of any major adverse cardiovascular event. Some secondary endpoints were reached that “require further analysis”, and the safety data showed no major imbalances; a second pivotal study now needs to succeed for this project to have legs.
The Stability trial was conducted in more than 15,000 patients with chronic coronary heart disease; Solid-Timi 52, which recruited more than 13,000 patients with acute coronary syndrome who had very recently experienced a heart attack or stroke, will report next year. Both trials were seeking to determine whether adding darapladib to standard therapy would reduce the risk of further cardiac events.
Lipoprotein-associated phospholipase A2 or Lp-PLA2 is an inflammatory enzyme thought to be involved in the formation of rupture-prone artery plaque, which can cause blood clots and trigger heart attacks or strokes. Darapladib blocks or reduces the activity levels of Lp-PLA2, so Glaxo was hoping to show that it could stabilise these patients’ sclerotic arteries and prevent cardiac events.
Less than conclusive phase II data made pushing this project into such large studies controversial. It failed to show a significant impact on measures such as C-reactive protein and plaque deformability, but did appear to arrest the growth of the necrotic core of atherosclerotic arteries, the area prone to rupture.
On top of scant clinical evidence, the validity of Lp-PLA2 as a risk marker and its actual role in heart disease are far from confirmed. Epidemiological data do appear to show an association between the activity of this enzyme and heart disease, but the actual mechanistic role it plays has yet to be fully elucidated.
Researchers have had exactly the same problem with therapies that boost HDL or so-called good cholesterol – seemingly incontrovertible epidemiological evidence of the beneficial impact of high HDL cannot be replicated in randomised clinical trials.
In this field only statins have managed to demonstrate a survival benefit and therefore support epidemiology data that suggest that high levels of LDL or “bad” cholesterol heightens the risk of heart problems. But it is not fully understood why even statins work; their pleiotropic or multiple mechanisms of action are now thought to lie at the root of the clinical benefit and it is clear that certain groups of people stand to benefit much more.
Glaxo will no doubt look for subgroups that did respond to darapladib. But unlike other therapy areas, particularly cancer, in which researchers are increasingly attempting to define and narrow patient populations using biomarkers or molecular signals, the cardiovascular world continues to rely on these huge, all-comer studies.
It is clear that the processes that contribute to a person’s cardiovascular risk profile need to be better understood, and markers more reliably interpreted, to give agents like darapladib a better chance of succeeding. Not only because of the clear clinical need, but also because such hugely expensive programmes weaken the pharma industry’s claims of improving R&D productivity.