The tale of CETP (cholesteryl ester transfer protein) as a drug target has been long, and convoluted, and expensive, and horrendously disappointing. Pfizer failed, Roche failed, several other companies like BMS who didn’t even get that far failed, and last fall Lilly’s entry failed, too (that link has links to several past blog posts here on the subject – I’ve been writing on the subject for over ten years now).
More details have now emerged about that most recent exercise in futility – and “clinical futility” was exactly what killed the compound off. And it’s quite interesting, in a disturbing way: Lilly’s evacetrapib did just you would want a CETP inhibitor, or any lipid-targeting cardiovascular drug, to do. It raised HDL by 130% compared to placebo, and lowered LDL by 35%. But the cardiovascular outcomes (MI, angina, stroke, and so on) were absolutely identical between the treatment group and the placebo group. At one point, if you’d asked cardiologists to predict the effects of a compound that affected cholesterol levels in this way, you’d have gotten some pretty enthusiastic guesses. But not now.
In the end, cholesterol, lipoproteins, and all the rest of the things you can get from blood work are merely surrogates for what really matters, which is how many people end up in the hospital and how many die. There’s a pretty good correlation between those numbers and low total cholesterol, and it’s widely believed that there’s a correlation with low LDL as well. And there’s evidence that high HDL is protective, too, thus all the talk of “good cholesterol” and “bad cholesterol”. But if you can raise HDL and lower LDL and still have no effect at all, then just how good are these markers?
There are several possibilities: perhaps the markers are OK, but CETP inhibitors do something else that cancels out the beneficial effects that they’re signaling. That was the thought with Pfizer’s torcetrapib, where the treatment group actually had higher mortality than the control group. Effects on blood pressure were seen, for example, and in this Lilly trial there was a small (but statistically discernable) rise in blood pressure as well. But it doesn’t seem to be enough to completely cancel out what the beneficial effects should be of more than doubling HDL, that’s for sure. It might also be that raising HDL and lowering LDL through this specific mechanism somehow doesn’t count, that it comes in the wrong place in the grand lipid-handling scheme to exert a beneficial effect.
Another possibility is that the markers are OK, as far as they go, but we’re not looking closely enough. HDL and LDL can be subdivided into further lipoprotein fractions, and maybe at that level of detail we can see the good good cholesterol as opposed the ordinary good cholesterol, etc. To the best of my knowledge, though, people have been digging around in the Pfizer and Roche data to see if they can make something of this idea, and I haven’t seen anything dramatic. But human lipid handling is extremely complex, and you can plausibly appeal to that at any point when things go wrong.
But that brings up a third possibility, that lipidology is complex enough to have fooled us completely, and that HDL and LDL are not, in fact, good markers at all. There’s a lot of room to argue against that – statins, for example, really do seem to have beneficial real-world outcomes over multiyear dosing. The counterargument is that not all of that is due to lowering LDL per se, that there are other effects (both on- and off-target) that we’re not taking account of. On the HDL side, you have human genetic mutant populations who have abnormally high levels, and do indeed seem to have protection from cardiovascular disease. These two lipoproteins have emerged as markers, then, for some pretty good reasons – but the CETP story is clear evidence that we’re missing something, or several things.
Several large companies have poured hundreds of millions of dollars apiece down the drain in finding this out for us. And Merck – last anyone heard – is supposedly pressing on. But man, you’d have to think that no one over there has a good feeling about this, with the whole CETP landscape lit up by piles of burning cash and striped with the shadows thrown by mounds of clinical debris. It’s a wasteland out there, badlands that have made every single company that’s ever entered the territory regret their actions deeply. And that’s where you’ll find Merck. For how much longer, one wonders?