So folks, let’s raise a bunch of money and pile back into CETP! You know, that great cardiovascular target that has been an absolute vale of tears for every big drug company that’s tried to develop it? What do you say?
Interestingly enough, someone is doing just that. I wrote last year about DalCor, a Montreal-based startup who had licensed Roche’s failed drug in this area, dalcetrapib. An analysis by Jean-Claude Tardif and co-workers of the dalcetrapib clinical data suggested that there actually were responders in the data set, specifically, people who were polymorphic for the ADCY9 gene. One genotype had a 39% lower rate of cardiovascular events in the drug treatment group, while another genotype had a 27% greater rate, and several other SNPs were associated with response to the drug as well. That would seem to be a pretty strong signal.
So what’s the gene? It codes for adenylate cyclase 9, a widely distributed form of the enzyme that’s been assoicated with several disease states, but not especially with cardiovascular problems. But there does appear to be some link with CETP inhibition, and there’s certainly enough evidence by now that our understanding of what’s going on with that therapy is. . .incomplete. Hundreds and hundreds of millions of dollars worth of incomplete, with trial after trial raising HDL, lowering LDL, and having no god efects whatsoever in cardiovascular outcomes.
The Montreal analysis was on carotid thickness, which is considered to be a pretty good marker for outcomes (better than lipoproteins, certainly). But you’re going to need about $250 million to put that idea to the test in the clinic, and that requires a goodly amount of nerve, considering the brutal history of this area. According to FiercePharma, DalCor is starting to recruit now for a 5,000-patient trial, though, and has raised perhaps $150 million of what they’ll need to get all the way through. Perhaps they’re hoping for some promising interim data to turbocharge the rest of the funding, and they might well be hoping to turn around and sign a deal with one of the large companies that have previously abandoned the field.
That’s going to require a good dose of those promising numbers. And it’s also going to require some promising figures on just how many patients will be able to take the drug. We already know that the broad population is not going to benefit (and odds are that Merck is going to tell everyone again next year, when their own CETP inhibitor trial reports at last). But how many variants of ADCY9 are going to show significant effects, and how many people have them? About 20% of the Roche dalcetrapib trial seem to have fallen into this category, so if that holds, you have to run the numbers with one-fifth of the expected patient population. On the other hand, those patients will be pretty close to guaranteed to experience a real benefit, assuming the trial works the way it’s theorized to, and you can identify them up front with a simple genetic marker. (A mechanism would be nice, too, but isn’t essential). So it might work, and there are plenty of companies with plenty of people who can run just those sorts of analyses. We shall see. . .