Here’s a look at something that doesn’t make many headlines: the apparent failure of an entire class of potential drugs. The insulin-like growth factor 1 receptor (IGF-1R) has been targeted for years now, from a number of different angles. There have been several antibodies tried against it, and companies have also tried small molecule approaches such as inhibiting the associated receptor kinase. (I was on such a project myself a few years back). So far, nothing has worked out.
And as that review shows, this was a very reasonable-sounding idea. Other growth factor receptors have been successful cancer targets (notably EGFR), and there was evidence of IGFR over-expression in several widespread cancer types (and evidence from mouse models that inhibiting it would have the desired effect). The rationale here was as solid as anything we have, but reality has had other ideas:
It is hardly surprising that even some of the field’s pioneers are now pessimistic. “In the case of IGF-1R, one can protest that proper studies have not yet been carried out,” writes Renato Baserga, from the department of Cancer Biology, Thomas Jefferson University in Philadelphia. (J. Cell. Physiol., doi:10.1002/jcp.24217). A pioneer in IGF-1 research, Baserga goes on to list some avenues that may still be promising, such as targeting the receptor to prevent metastases in colorectal cancer patients. But in the end, he surmises: “These excuses are poor excuses, [they are] an attempt to reinvigorate a procedure that has failed.” Saltz agrees. “This may be the end of the story,” he says. “At one point, there were more than ten companies developing these drugs; now this may be the last one that gets put on the shelf.”
But, except for articles like these in journals like Nature Biotechnology, or mentions on web sites like this one, no one really hears about this sort of thing. We’ve talked about this phenomenon before; there’s a substantial list of drug targets that looked very promising, got a lot of attention for years, but never delivered any sort of drug at all. Negative results don’t make for much of a headline in the popular press, especially when the story develops over a multi-year period.
I think it would be worthwhile for people to hear about this, though. I once talked with someone who was quite anxious about an upcoming plane trip; they were worried on safety grounds. It occurred to me that if there were a small speaker on this person’s desk announcing all the flights that had landed safely around the country (or around the world), that a few days of that might actually have an effect. Hundreds, thousands of announcements, over and over: “Flight XXX has landed safely in Omaha. Flight YYY has landed safely in Seoul. Flight ZZZ has landed safely in Amsterdam. . .” Such a speaker system wouldn’t shut up for long suring any given day, that’s for sure, and it would emphasize the sheer volume of successful air travel that takes place each day, over and over.
On the other hand, almost all drug research programs, or never even make it off the ground in the first place. In this field, actually getting a plane together, getting it into the air, and guiding it to a landing at the FDA only happens once in a rather long while, which is why there are plenty of people out there in early research who’ve never worked on anything that’s made it to market. A list of all the programs that failed would be instructive, and might get across how difficult finding a drug really is, but no one’s going to be able to put one of those together. Companies don’t even announce the vast majority of their preclinical failures; they’re below everyone else’s limit of detection. I can tell you for sure that most of the non-delivering programs I’ve worked on have never seen daylight of any sort. They just quietly disappeared.