Increases in HDL are only clinically meaningful when they increase reverse lipid transport (RLT). CETP inhibition blocks four of five ways HDL offloads collected fats, leaving only one of the more inefficient methods.
If you think of HDL as a garbage bag for bad lipids, CETP inhibitors cause the body to create lots of full garbage bags but make it so there are few places to empty them. Eventually the garbage bags degrade and the lipids are returned to the system.
So despite significant increases in HDL particles, you get no clinical efficacy. Avant, Japan Tobacco, and now Pfizer have all failed with this class of drug.
The only hope torcetrapib had is if Pfizer threaded a narrow pharmacokinetic needle. CETP-inhibition causes the body to create high numbers of HDL molecules, probably in reaction to the low amount of fat being offloaded. Once this is accomplished, however, you have to cease the CETP-inhibition so all the full garbage bags have someplace to offload.
The trick is to inhibit just long enough for an HDL boost but not too long to hamper RLT. I've always believed this PK needle was too small to thread in broad Phase III trials. There simply is too much inter-patient variance in compliance, fat intake, body chemistry, etc.
Unless otherwise indicated, this is the personal viewpoint of David Miller and not necessarily that of Biotech Stock Research, LLC
