More than six years after Pfizer famously abandoned a drug that was designed to raise HDL, or good, cholesterol, Roche is now making the same move. The drugmaker this morning released a brief statement saying that an independent Data and Safety Monitoring Board recommended stopping a Phase III study of some 15,000 patients for its dalcetrapib medication due to a lack of clinically meaningful efficacy.
"Lowering cardiovascular risk beyond that which is achieved with intensive statin treatment is a very challenging goal and while we have always stated that dalcetrapib is a high-risk project, we are disappointed by the fact that this drug didn't provide benefit to the patients in our study,” Hal Barron, the Roche chief medical officer and head of global product development, says in the statement (see here).
The move is a big blow to Roche, which previously cited the drug as one of nine forthcoming medicines with potential blockbuster sales potential. Dalcetrapib "was potentially one of the largest new assets they had in the late-stage pipeline,” Karl Heinz Koch, an analyst at Helvea, tells Bloomberg News. “In that sense it does leave a large gap." Roche stock plummeted on the news.
At the same time, the decision may have the potential to raise doubts about similar drugs that are being developed by Merck and Eli Lilly. Both medicines are also CETP inhibitors, although study results have been more upbeat. For instance, a trial of 1,623 people with coronary heart disease or an equivalent risk found the Merck pill, called anacetrapib, lowered LDL, or bad choleserol, while also raising HDL by 138 percent in patients already treated with a statin (read here).
"Dalcetrapib is a weak CETP inhibitor that only modestly increases HDL and doesn’t lower LDL. I’m not surprised that it failed to show benefit. The other two contenders, anacetrapib and (Lilly's) evacetrapib, are much more effective at raising HDL. Both the Merck and Lilly drugs also substantially lower LDL (about 35 percent to 40 percent). Dalcetrapib had no effect on LDL. I think that these more potent CETP inhibitors still have a good chance for success. No guarantees, but I’m reasonably optimistic," Steve Nissen, chairman of cardiology at the Cleveland Clinic and head of Eli Lilly’s CETP trial, writes us.
A larger issue, though, is the extent to which research should focus on raising HDL, a debate that has persisted ever since Pfizer walked away from torcetrapib (see this and this). A year ago, results of an Abbott Laboratories study also raised questions about raising HDL. The purpose was to test the theory that giving Niaspan to patients with HDL levels that were under control would experience an added benefit, but the risk of ischemic events may have been raised (back story). By making the same move, Roche may only underscore investor jitters.
"Based on the experimental data, I have always felt that dalcetrapib was the weakest of the CETP inhibitors in the clinic," John LaMattina, who was the Pfizer R&D chief from 2004 to 2007, writes us. "I think that Merck’s anacetrpib is the best compound out there and their outcomes trial will provide some answers as to whether CETP inhibition has long term benefits in reducing heart attacks and strokes.
"However, even if anacetrapib works clinically, it may not answer the question as to whether raising HDL is cardioprotective. That’s because anacetrapib not only raises HDL dramatically, but it also lowers LDL another 15 percent to 20 percent on top of atorvastatin’s LDL lowering capability. While patients will benefit from a positive outcome with anacetrapib, the exact reason for it (HDL? LDL? both?) won’t be known."
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