Last month, Amgen purchased a Dutch biotech firm, Dezima for $300 million upfront and potential milestones of $1.25 billion. A key to this buyout was TA-8995, a member of a class of heart drugs known as CETP inhibitors. This class of compounds generated enormous excitement a decade ago, thanks to the very promising lipid modulating effects these compounds possessed. The lead drug at the time, Pfizer’s torcetrapib, not only lowered LDL-cholesterol (LDL) but it simultaneously raised HDL-cholesterol (HDL) by 100%, an unprecedented finding at the time. Torcetrapib essentially remodeled one’s blood lipid profile bringing the LDL and HDL levels of heart patients into recommended ranges thereby offering the promise of reducing heart attacks and strokes in heart patients with, or at risk of, heart disease. It is no exaggeration to say that torcetrapib was one of the most exciting drugs in the entire biopharmaceutical industry’s pipeline.
But a funny thing happened on the way to the launch of this potential mega-blockbuster. To prove the value of torcetrapib, Pfizer ran a billion dollar phase 3 development program which had as its corner stone, the ILLUMINATE trial, a cardiovascular outcomes trial (CVOT) designed to show that torcetrapib plus atorvastatin (Lipitor) was superior to atorvastatin alone in reducing heart attacks and strokes in people with heart disease. On December 1, 2006 Pfizer halted ILLUMINATE based on the recommendation of an independent data safety monitoring board (DSMB) which said that the trial should stop due to an increase in all-cause mortality in the torcetrapib arm of the study. Pfizer ended the torcetrapib program and, in fact, dropped all HDL research the following year.
Now, nearly 9 years later, history has repeated itself. Despite the torcetrapib failure, others have soldiered on with their own CETP inhibitors, including Merck (with anacetrapib) and Lilly (evacetrapib). The rationale for these companies to continue on their seductive quest for the next generation lipid modulating pill, was that torcetrapib was a flawed molecule and that the CETP hypothesis could still be proven valid with the right molecule. Unfortunately, that may not be the case. Lilly announced this morning that they have discontinued development of evacetrapib. This came following the recommendation of the DSMB responsible for ACCELERATE, Lilly’s CVOT trial in patients with high-risk atherosclerotic heart disease. The DSMB believes that evacetrapib will not meet the study’s goal of reducing cardiovascular events in these heart patients.
Merck’s own CVOT study with anacetrapib, known as REVEAL, is continuing. Based on today’s announcement with evacetrapib, it is hard to envision that REVEAL will prove any different from ILLUMINATE or ACCELERATE, thereby drawing a close on the CETP field of R&D. Or will it? Just last month, Amgen spent $300 million on TA-8995, believing that this compound had a potency advantage over all other CETP inhibitors. Amgen appeared to be willing to press ahead in the CETP field despite being years behind in the chase. Now, it is only behind Merck. Will Amgen be willing to press ahead with a phase 3 program with TA-8995 that, including the obligatory CVOT trial, has a price tag in excess of $500 million? In light of today’s Lilly announcement, Amgen should cut its loses and drop the program.
(The author is the former head of Pfizer R&D and still owns Pfizer stock.)
