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A new company is betting hundreds of millions of dollars that it can snatch victory from the jaws of cholesterol ester transfer protein (CETP) inhibitor defeat.
Over the last decade, no class of drugs has undergone a reversal of fortune as dramatic as this once highly-promising class of drugs, which engendered comparison to statins at one point. But after the failure of torcetrapib in the ILLUMINATE trial, dalcetrapib in the dal-OUTCOMES trial, and, just recently, evacetrapib in the ACCELERATE trial, most observers abandoned all hope for the drugs.
The new company, DalCor, has raised $150 million to pursue the development of dalcetrapib "in a genetically distinct population of patients with cardiovascular disease," according to a company press release.
Those hopes are pinned on a genetic substudy of dal-OUTCOMES, published last year in Circulation: Cardiovascular Genetics, that found a single genetic polymorphism that identified patients in the dal-OUTCOMES trial who were likely to benefit from dalcetrapib. Patients treated with dalcetrapib who had the AA genotype of the ADCY9 gene had a 39% reduction in cardiovascular events. By contrast, patients with the GG genotype had a 27% increase in events. The authors, led by Jean-Claude Tardif, MD, of the Montreal Heart Institute, calculated that about 20% of patients have the AA genotype and could benefit from dalcetrapib.
DalCor has now secured the rights to market dalcetrapib along with the rights to the genetic marker, the company said. The company will soon announce the start of the dal-GenE study, in which 5,000 ACS patients with the AA genotype will be randomized to dalcetrapib or placebo. Tardif is a principal investigator of the trial.
But some skeptics point to the small number of absolute events in the genetic substudy: Among the AA patients who received dalcetrapib there were 38 who had events and 447 without events. In the placebo group the corresponding numbers were 59 and 416.
Even one company supporter, Alan Tall, MD, of Columbia University in New York City, who serves as an adviser to DalCor and has not given up on CETP inhibition, acknowledged that this "is a weakness of this post-hoc analysis."
Tall remained hopeful, however. He called it premature to view the recent ACCELERATE trial as a "slam dunk negative" since that trial might not have run long enough to demonstrate benefit associated with evacetrapib. Further, as the genetic study suggests, a genuine benefit in one genotype might be masked in the overall trial population by a negative effect of a genotype with the opposite effect.
Tall acknowledged another weakness, which is the lack of any obvious functional relationship linking the ADCY9 gene to the mechanism of CETP. That is still "a big black hole," said Tall. "There's a lot of work that needs to be done; the function of this gene needs to be better understood."
Marc Pfeffer, MD, PhD, of Brigham and Women's Hospital in Boston, is a consultant to DalCor and has equity in the company. In an interview, he explained how he became involved as a result of his role as the chair of the data safety monitoring board of the dal-OUTCOMES trial. Because of the earlier problems with torcetrapib, his committee took great care to monitor the safety of dalcetrapib during the trial. Ultimately the trial was terminated due to futility, but "although we weren't seeing benefit, we weren't seeing harm," said Pfeffer.
Pfeffer said he was fascinated when Tardif later showed him the results of the genetic study. If the idea behind DalCor is true, then "it's remarkable and important. It would be what everybody has been looking for -- a drug guided by the genes," he said.
Pfeffer emphasized a unique and important advantage in DalCor's favor. Because dalcetrapib has been shown to be safe in a large clinical trial, they can jump almost immediately into a large phase III trial. "I can't tell you whether this will work in this genotype, but I can tell you it will be safe."
Pfeffer said he understands that the trial might not succeed but is not concerned, "because we know there are no safety issues, and we know the dose. The trial we're doing is sized for hard outcomes."
Pfeffer continued: "This observation has to be pursued. The possibility of reducing risk by 20% to 25% in a safe manner should not be left on the table."
But at least one outside observer thinks the company is misguided. Sekar Kathiresan, MD, of Massachusetts General Hospital and the Broad Institute, pointed out that the statistically-significant results of the genetics study are not terribly impressive, given that the investigators examined a million different SNPs. "This is literally betting $150 million on a P-value of 0.04 in one hypothesis-generating study," Kathiresan said in an interview. "The genetic data are intriguing but just on the margin of significance for all the testing they did."
Kathiresan said he "wouldn't spend another dime on CETP, but clearly they have convinced people that this is potentially a worthwhile investment."
Kathiresan cast doubt on biologically plausibility of the underlying principle. "I just don't think that that kind of thing is what happens in biology," he said. He compared ADCY9 to the earlier story with CYPC19, which is known to play an important role in clopidogrel (Plavix) metabolism. "Even in a simpler situation [like CYPC19], where the variant actually affects the biology -- even in that context the variant has a barely noticeable effect on outcome. Now, to go one step further, we don't know what the gene does." A very large effect is "not plausible," he said.
Jim Stein, MD, of the University of Wisconsin in Madison, said he doesn't know whether the trial will be successful but that it's raising some important questions:
"It's a fantastic idea and great science that will blaze a trail even if unsuccessful ultimately. If it is eventually successful, it will prove a concept for a whole new paradigm for drug discovery and re-assessment of old, 'failed' agents. But it is immensely risky financially. I can't imagine how this approach would be profitable, though in the future, one never knows. For example, if we can develop rapid and inexpensive genetic screening, it could facilitate this approach. There are other medications that are used or not used in people with certain genetic polymorphisms. There are a lot of hurdles to overcome, but it is great to see some progress in this direction."