CETP Inhibitors: Blockbusters that Never Ran?

The news that Roche scrapped development on its CETP inhibitor dalcetrapib, a drug designed to raise HDL cholesterol in the blood, likely presages the shuttering of Lilly’s development program for its CETP inhibitor, evacetrapib, industry experts and analysts say.

Merck’s CETP inhibitor, anacetrapib, will probably receive additional scrutiny as well, although Tim Anderson, senior analyst at Bernstein Research, identified a “bull case” for the product in an analyst note. The argument in favor of anacetrapib, per Anderson, hinges on the drug’s apparent lack of safety problems compared with torcetrapib (Pfizer’s CETP inhibitor that hit a developmental dead end due to safety problems in 2006), and the fact that it lowers LDL cholesterol, whereas Roche’s dalcetrapib only raised HDL. At any rate, Merck’s Phase 3 trial “is not likely to conclude for two or three years, in the best of circumstances,” wrote Anderson.

The CETP inhibitors—those still being developed—are justified by the assumption that raising HDL levels correlates with a lowering of cardiovascular risk. Donald McCaffrey, CEO at Resverlogix, a Canadian biotech firm, says with HDL, it’s all about “reverse cholesterol transport,” or in other words, plaque removal from the arteries. With HDL, “it’s not about the huge numbers, as Roche’s program has just shown. It’s about functional HDL…and whether you can make more of it.” A simple blood plasma test can show that a patient has higher levels of HDL, says McCaffrey, but HDL differs in function and capability. Resverlogix is developing a product (RVX-208) that acts on the “main protein” in HDL, known as ApoA-1 protein. By causing the body to make more of the ApoA-1 protein, more HDL is created, but it’s “empty” HDL. The idea is to “take the garbage out of the arteries, which requires more garbage bags.” With CETPs, the approach is to stop HDL from leaving the system, which causes it to build up. But the HDL build-up in that scenario resembles a garbage dump. That kind of HDL is “not going to go back into that arterial wall and take out any more plaque…it cannot,” says McCaffrey.

Another concern for CETP inhibitor programs is the class-wide effect of increased C-reactive protein (CRP) levels, a “very serious” inflammation marker, according to McCaffrey. “If you’re increasing your HDL, and you’re increasing CRP, that has been deemed a serious problem,” he says. Lilly and Merck’s respective CETP inhibitors have both demonstrated CRP increases; Lilly’s evacetrapib had the largest increase, followed by Merck’s anacetrapib, and then, in third, Roche’s dalcetrapib. McCaffrey claims that RVX-208, his company’s product, decreases CRP levels by 28%. RVX-208 is currently in two Phase 2 trials, both of which are being conducted by the Cleveland Clinic. The ASSURE trial, which aims to demonstrate plaque regression, not just an HDL increase, is expected to be complete by the first quarter of 2013. The drug is being tested in combination with atorvastatin and rosuvastatin—Lipitor and Crestor, respectively—because “we believe they will be the most efficient statins in the generic market.”

McCaffrey agrees with Anderson on the fate of evacetrapib: “I think the board in Lilly’s case is very conservative, so I think they’ll probably shelve [evacetrapib].” As for Merck’s anacetrapib, “they’ll probably continue on, they’re deep into that program and I think they need to find an answer,” says McCaffrey. (Norman Wong, Resverlogix’s chief scientific officer, outlined the problem with CETP inhibitors in a white paper published last November.)

Analysts have long predicted blockbuster sales for the CETP inhibitor class of drugs, and yet, none have made it through to approval. With the closure of Roche’s dalcetrapib program, is there enough blockbuster potential remaining to justify the enormous development costs these drugs require?

Written by Ben Comer for Pharmaceutical Executive.