On May 7th 2012, Roche terminated the entire dal-HEART phase III programme looking at the effects of their CETP inhibitor dalcetrapib in patients with acute coronary syndrome. The immediate cause was the report from the data management committee of the dal-OUTCOMES trial in 15,000 patients that there was now no chance of reporting a 15% benefit with the drug.
The market reacted in surprise and disappointment and immediately trimmed $5billion of the market capitalization of Roche. After all, here was a class of drugs that had been trumpeted by the pharma industry as the next “super-blockbusters” to follow the now-generic statins. The data from dal-OUTCOMES has dealt that dream a fatal blow.
The important lesson, however, is that such a painful and expensive failure was entirely preventable, because the dream itself was built on a fundamentally flawed understanding of biomarkers. And that’s not speaking with the benefit of hindsight: we predicted this failure back in January 2012 in the DrugBaron blog.
On May 7th 2012, Roche terminated the entire dal-HEART phase III programme looking at the effects of their CETP inhibitor dalcetrapib in patients with acute coronary syndrome. The immediate cause was the report from the data management committee of the dal-OUTCOMES trial in 15,000 patients that there was now no chance of reporting a 15% benefit with the drug.
The market reacted in surprise and disappointment and immediately trimmed $5billion of the market capitalization of Roche. After all, here was a class of drugs that had been trumpeted by the pharma industry as the next “super-blockbusters” to follow the now-generic statins. The data from dal-OUTCOMES has dealt that dream a fatal blow.
The important lesson, however, is that such a painful and expensive failure was entirely preventable, because the dream itself was built on a fundamentally flawed understanding of biomarkers. And that’s not speaking with the benefit of hindsight: we predicted this failure back in January 2012 in the DrugBaron blog.
CETP inhibitors boost HDL (the so-called “good cholesterol”) by inhibiting the Cholesterol Ester Transfer Protein (CETP), a key enzyme in lipoprotein metabolism. And they work! HDL cholesterol concentrations are doubled soon after beginning treatment, more than reversing the depressed HDL levels that are robustly associated with coronary heart disease (and indeed risk of death from a heart attack).
That was quite a firm enough foundation for developers to believe that CETP inhibitors had a golden future. After all, HDL is the “best” biomarker for heart disease. By that I mean that, of all the lipid measures, HDL gives the strongest association with heart disease in cross-sectional studies and is the strongest predictor of future events in prospective studies. Since we know lipids are important in heart disease (from years of clinical experience with statins), therefore elevating HDL with CETP inhibitors just HAS to work. Right?
Wrong.
Strength of an association is just one factor in the decision as to whether a biomarker and an outcome are linked. Unfortunately, Sir Austin Bradford Hill put it first in his seminal list of criteria published in 1963 and still widely used today. And he didn’t provide a strong enough warning, it seems, that it is only one factor out of nine that he listed. Total Scientific updated those criteria for assessing modern biomarker data in 2011, and stressed how the strength of an association could be misleading, but obviously that was too late for Roche who were already committed to a vast Phase 3 programme.
Here’s the problem with HDL. HDL cholesterol concentrations are temporally very stable – they do not change a great deal from one day to the next, or even for that matter from one month to the next. A single (so-called ‘spot’) measure of HDL cholesterol concentration, therefore, represents an excellent estimate of the average concentration for that individual over a substantial period.
Other lipid parameters do not share this characteristic. Triglyceride concentration, for example, changes not just day by day but hour by hour. Immediately following a meal, triglyceride levels rise dramatically, with the kinetics and extent of the change dependent on the dietary composition of the food and the current physiological status of the individual.
These temporal variation patterns bias how useful a spot measure of a biomarker is for a particular application. If you want to predict hunger or mood (or anything else that varies on an hour-by-hour timescale) triglycerides will have the advantage – after all, if HDL doesn’t change for weeks it can hardly predict something like hunger. By contrast, if you want to predict something like heart disease that is a very slowly progressing phenotype, the same bias favours a spot measure of HDL over a spot measure of triglycerides.
HDL cholesterol concentration, then, as a biomarker has an in-built advantage as a predictor of heart disease IRREPESECTIVE of how tightly associated the two really are, and most critically IRRESPECTIVE of whether there is a real causative relationship between low HDL and cardiovascular disease.
All this matters a great deal because all the lipid parameters we measure are closely inter-related: low HDL is strongly associated with an elevated (on average) triglyceride and LDL. For diagnosing patients at risk of heart disease you simply pick the strongest associate (HDL), but for therapeutic strategies you need to understand which components of lipid metabolism are actually causing the heart disease (while the others are just associated as a consequence of the internal links within the lipid metabolism network).
Picking HDL as a causative factor primarily on the basis of the strength of the association was, therefore, a dangerous bet – and, as it turns out, led some very expensive mistakes.
Okay, so the structural bias towards HDL should have sounded the alarm bells, but surely it doesn’t mean that HDL isn’t an important causative factor in heart disease? Absolutely correct.
But this isn’t the first “death” for the CETP Inhibitor class. As DrugBaron pointed out, the class seemed moribund in 2006 when the leading development candidate, Pfizer’s torcetrapib, failed to show any signs of efficacy in Phase 3.
As so often happens, when observers attempted to rationalize what had happened, they found a ‘reason’ for the failure: they focused on the small but significant hypertensive effect of torcetrapib – a molecule-specific liability. An argument was constructed that an increase in cardiovascular events due to this small increase in blood pressure must have cancelled out the benefit due to elevated HDL.
That never seemed all that plausible – unless you were already so immersed in ‘the HDL myth’ that you simply couldn’t believe it wasn’t important. To those of us who understood the structural bias in favour of HDL as a biomarker, the torcetrapib data was a strong premonition of what was to come.
So strong was ‘the HDL myth’ that voices pointing out the issues were drowned out by the bulls who were focused on the ‘super-blockbuster’ potential of the CETP inhibitor class. Roche were not the only ones who continued to believe: Merck have a similar programme still running with their CETP Inhibitor, anacetrapib. Even the early data from that programme isn’t encouraging – there is still no hint of efficacy, although they rightly point out that there have not yet been enough events analysed to have a definitive answer.
But the signs are not at all hopeful. More than likely in 2012 we will have the painful spectacle of two of the largest Phase 3 programmes in the industry failing. Failures on this scale are the biggest single factor dragging down R&D productivity in big pharmaceutical companies.
Surely the worst aspect is that these outcomes were predictable. What was missing was a proper understanding of biomarkers and what they tell us (or, perhaps in this case, what they CANNOT tell us). Biomarkers are incredibly powerful, and their use is proliferating across the whole drug development pathway from the bench to the marketplace. But like any powerful tool, they can be dangerous if they are misused, as Roche (and their investors) have found to their substantial cost. Total Scientific exist to provide expert biomarker services to the pharmaceutical industry – let’s hope that not bringing in the experts to run your biomarker programme doesn’t cost you as much as it did Roche.
Dr. David Grainger
CBO, Total Scientific
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RxCelerate Ltd is an outsourced drug development platform based near Cambridge, UK. We specialize in delivering an entire road map of drug development services from discovery and medicinal chemistry through to formal preclinical development and clinical up to Phase IIa. In the last five years, we have witnessed dramatic changes in the drug development …
