Hardly anybody wants new drugs that act like a sledgehammer, bashing diseased and healthy cells like old-school cancer chemotherapy. Many drugs today are supposed to be smart enough to work like laser-guided missiles that hit the diseased cells and mostly spare the healthy ones.
But if your goal is to create one of these amazing “targeted” therapies, you’ve got to start by having a great biological target to aim at in the first place. These are the protein receptors on the cell surface, the enzymes that perform dirty work inside cells, the signaling pathways that cells use to send messages, or the RNA sequences that give rise to bad proteins. Much as the biologists can study these targets, nobody really knows for sure what will happen—good and bad—until a drug to inhibit the target’s activity gets tested in human beings.
Writing about biological targets is not an easy thing. Scientists have some funny naming habits and love acronyms as much as your average federal agency. But it’s worth cutting through some of that fog, because there are cool things happening now in biology to help us better understand the genetic and environmental factors that combine to make us diseased or healthy. As the genomics researcher Daniel MacArthur wrote on Twitter this week: “The present period is the most exciting time ever in the history of biology. True or false? If not now, when?”
I agree, so I thought it would be worthwhile to ask a few industry leaders to offer advice on what science says are the hottest biological targets for drug development today. For the purposes of this exercise, “hot” doesn’t necessarily mean “best”—only that there’s intense interest in the target by at least a handful of companies making drugs against it. This is also not about listing the most proven biological targets—HER2, VEGF, TNF, EGFR and more. This is just a short list of targets that are currently generating a lot of interest in development today, and which I think you’re going to see discussed a lot in the news. If you’ve got other targets you’d like to add to the list, please post a comment at the end of this article, or send me a note at [email protected].
Without further ado, here goes:
PCSK9: This enzyme target has gained a lot of momentum in the past year as the next big thing for fighting cardiovascular disease, by lowering cholesterol. The idea here is that when people have an overactive form of PCSK9, it reduces the number of LDL cholesterol receptors that appear on the surface of their liver cells. When you have fewer of those receptors, it becomes more difficult to break down the LDL that comes from your average cheeseburger, causing the cholesterol to build up in the bloodstream. On the flip side, researchers have shown that people with certain mutations that limit PCSK9 activity are naturally able to keep their cholesterol quite low.
Once that was established in 2005 and 2006—as Bloomberg summed up in a feature last November—it was off to the races. The bar is high for drug developers since statin drugs are now cheap, generic, and quite effective, but many companies believe PCSK9 drugs will work in patients who don’t get enough benefit from statins alone. Contenders in this competition include various targeted drugs from Amgen, a collaboration between Sanofi and Regeneron Pharmaceuticals, Pfizer, Merck, and Alnylam Pharmaceuticals.
“At this point, it’s the most exciting target in the cardiovascular field,” says Roger Perlmutter, the former executive vice president of R&D at Amgen. “The human genetic data are powerful, and data from both Regeneron/Sanofi and Amgen demonstrate impressive LDL cholesterol lowering in phase 1/2 clinical trials.”
PI3 kinase: This has been one of the hot targets in cancer biology for years. The PI3 kinase pathway has been shown to be involved in critical processes like cell proliferation, differentiation, migration, and survival. When these normal functions get flipped into an overactive mode, it’s a key step on the journey for cancer cells that grow out of control. Once the PI3 kinase machinery is out of whack, other enzyme targets can go off-kilter downstream, too, like AKT and mTOR.
There hasn’t been a big Phase III clinical trial yet
